U.S. patent number 8,003,806 [Application Number 11/270,088] was granted by the patent office on 2011-08-23 for integrin antagonists useful as anticancer agents.
This patent grant is currently assigned to OSI Pharmaceuticals, LLC. Invention is credited to Jason Bloxham, Gary V. Borzillo, Eric William Collington, Shazia Sadiq, Colin Peter Sambrook Smith, Chris L. Waller, Graham M. Wynne.
United States Patent |
8,003,806 |
Bloxham , et al. |
August 23, 2011 |
Integrin antagonists useful as anticancer agents
Abstract
The invention relates to compounds of the Formula 1 ##STR00001##
and to pharmaceutically acceptable salts and solvates thereof,
wherein A, X.sup.2, X.sup.4, X.sup.5 and X.sup.1 are as defined
herein. The invention also relates to methods of treating abnormal
cell growth in mammals by administering the compounds of Formula 1
and to pharmaceutical compositions for treating such disorders
which contain the compounds of Formula 1.
Inventors: |
Bloxham; Jason (Oxford,
GB), Borzillo; Gary V. (Farmingdale, NY),
Collington; Eric William (Oxford, GB), Sadiq;
Shazia (Oxford, GB), Sambrook Smith; Colin Peter
(Oxford, GB), Waller; Chris L. (Farmingdale, NY),
Wynne; Graham M. (Oxford, GB) |
Assignee: |
OSI Pharmaceuticals, LLC
(Farmingdale, NY)
|
Family
ID: |
36337327 |
Appl.
No.: |
11/270,088 |
Filed: |
November 9, 2005 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20060116383 A1 |
Jun 1, 2006 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60627775 |
Nov 12, 2004 |
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Current U.S.
Class: |
548/310.1;
544/238; 548/127; 544/370; 544/333; 546/199; 546/169; 546/146;
544/262; 546/273.4; 548/248; 544/182; 548/181 |
Current CPC
Class: |
C07D
235/06 (20130101); C07D 401/14 (20130101); C07D
487/04 (20130101); A61P 35/00 (20180101); C07D
405/12 (20130101); C07D 403/12 (20130101); C07D
405/14 (20130101); C07D 401/06 (20130101); C07D
409/12 (20130101); C07D 413/12 (20130101); C07D
417/12 (20130101); C07D 409/14 (20130101); C07D
417/14 (20130101); C07D 401/04 (20130101); C07D
403/04 (20130101); C07D 401/12 (20130101) |
Current International
Class: |
A61K
31/4184 (20060101); C07D 235/04 (20060101) |
Field of
Search: |
;548/310.1 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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WO-97/10219 |
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Mar 1997 |
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WO |
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00/51608 |
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Sep 2000 |
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WO |
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00/68188 |
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Nov 2000 |
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WO |
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01/94311 |
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Dec 2001 |
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WO |
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02/18377 |
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Mar 2002 |
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WO |
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03/041708 |
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May 2003 |
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WO |
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2004/074284 |
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Sep 2004 |
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WO |
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2004/099192 |
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Nov 2004 |
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WO |
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2006/034418 |
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Mar 2006 |
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WO |
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2006021418 |
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Mar 2006 |
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WO |
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Other References
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compounds with RN 40332-16-9, 14840-18-7 abstract & Zhongguo
Yaowu Huaxue Zazhi, 11 (5), 259-262 Coden: Zyhzef; ISSN: 1005-0108,
2001. cited by other .
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cited by other .
Souillac, P. et al. (1999) Characterization of Delivery Systems,
Differential Scanning Calorimetry in Encyclopedia of Controlled
Drug Delivery, John Wiley & Sons, pp. 212-227. cited by other
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Vippagunta, S.R. et al. (2001) Advanced Drug Delivery Reviews
48:3-26. cited by other .
Yadav-Bhatnagar, N. et al. (2002) Journal of Combinatorial
Chemistry 4(1):49-55. cited by other .
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PCT/US2005/042048, May 15, 2007. cited by other .
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Tan, R. et al. (2001) Zhongguo Yaowu Huaxue Zazhi, 11 (5), 259-262
*Non english--includes English abstract, Chinese Journal of
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PCT/US2005/042048, Jun. 15, 2006. cited by other.
|
Primary Examiner: Stockton; Laura L.
Attorney, Agent or Firm: Rafa; Michael J. OSI
Pharmaceuticals, LLC
Parent Case Text
This application claims the benefit of U.S. Provisional App. No.
60/627,775, filed Nov. 12, 2004, which is herein incorporated by
reference in its entirety.
Claims
The invention claimed is:
1. A compound of Formula 1 ##STR00127## or a pharmaceutically
acceptable salt, wherein: the dashed line designates that a double
bond or a single bond connects the nitrogen at the three position
with the carbon at the two position; each A and A' is independently
a direct bond, --C(O)N(R.sup.4)--, --N(R.sup.4)C(O)--,
--N(R.sup.4)SO.sub.2--, --SO.sub.2N(R.sup.4)--,
--N(R.sup.4)C(O)(CR.sup.4R.sup.5).sub.pNHC(O)--,
--N(R.sup.4)C(O)(CR.sup.4R.sup.5).sub.pN(R.sup.4)--,
--N(R.sup.4)C(S)(CR.sup.4R.sup.5).sub.pN(R.sup.4)--,
--N(R.sup.4)C(O)(CR.sup.4R.sup.5).sub.pC(O)--, --N(R.sup.4)C(O)O--,
--N(R.sup.4)C(O)S--, --C(O)--, --N(R.sup.3)--, --S-- or --O--,
wherein p is an integer from 0 to 5 and the left dash of the
foregoing groups is attached to the benzimidazole ring of the
compound of Formula 1; X.sup.1 is
--CH.sub.2--CH(AR.sup.1)--CO.sub.2H,
--CH(AR.sup.1)--CH.sub.2--CO.sub.2H or
--C(AR.sup.1).dbd.CHCO.sub.2H; X.sup.2 is H, C.sub.1-C.sub.20
alkyl, C.sub.2-C.sub.20 alkenyl, C.sub.2-C.sub.20 alkynyl,
--(CR.sup.4R.sup.5).sub.t(C.sub.3-C.sub.20 cycloalkyl),
--(CR.sup.4R.sup.5).sub.t(C.sub.6-C.sub.10 aryl), or
--(CR.sup.4R.sup.5).sub.t(4 to 12 membered heterocyclic), wherein
each X.sup.2 group, except H, is substituted by X.sup.3, each t is
independently an integer from 0 to 5, said alkyl, alkenyl and
alkynyl groups optionally contain 1 or 2 hetero moieties selected
from O, --S(O).sub.j-- wherein j is an integer from 0 to 2, and
--N(R.sup.4)-- with the proviso that two O atoms, two S atoms, or
an O and S atom are not attached directly to each other, and the
proviso that an O atom, a S atom or a N atom are not attached
directly to a triple bond or non-aromatic double bond; said
cycloalkyl, aryl and heterocyclic X.sup.2 groups are optionally
fused to one or two ring systems independently selected from a
benzene ring, a C.sub.5-C.sub.8 cycloalkyl group, and a 4 to 10
membered heterocyclic group; --(CR.sup.4R.sup.5).sub.t-- optionally
includes a carbon-carbon double or triple bond where t is an
integer from 2 to 5, or where t is 1 the
--(CR.sup.4R.sup.5).sub.t-- moiety of --(CR.sup.4R.sup.5).sub.t(4
to 12 membered heterocyclic) and
--(CR.sup.4R.sup.5).sub.t(C.sub.3-C.sub.20 cycloalkyl) optionally
is attached by a carbon-carbon double bond to a carbon of the
cycloalkyl group or a non-aromatic carbon of the 4 to 12 membered
heterocyclic group; said cycloalkyl optionally includes one or two
carbon-carbon double or triple bonds; and X.sup.2, except when H,
optionally is substituted by 1 to 5 R.sup.2 groups; X.sup.3 is H,
2-aminoimidazoyl, 2-aminobenzimidazoyl, 2-aminopyridyl,
2-aminopyrimidyl, or 2-aminopyrazinyl, wherein X.sup.3, except when
H, optionally is substituted by 1 or 2 R.sup.2 groups; X.sup.4 is
H, C.sub.1-C.sub.10 alkyl, --NR.sup.3R.sup.4, --SR.sup.3, or
--OR.sup.3; each X.sup.5 and R.sup.2 is independently selected from
C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10
alkynyl, halo, cyano, nitro, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, azido, --OR.sup.3, --C(O)R.sup.3, --C(O)OR.sup.3,
--NR.sup.4C(O)OR.sup.6, --NR.sup.4C(O)R.sup.3, --OC(O)R.sup.3,
--NR.sup.4SO.sub.2R.sup.6, --SO.sub.2NR.sup.3R.sup.4,
--NR.sup.4C(O)R.sup.3, --C(O)NR.sup.3R.sup.4,
--O--N.dbd.CR.sup.3R.sup.4, --NR.sup.4C(O)NR.sup.3R.sup.4,
--NR.sup.4C(S)NR.sup.3R.sup.4, --NR.sup.3R.sup.4,
--S(O).sub.j(CR.sup.4R.sup.5).sub.t(C.sub.6-C.sub.10 aryl),
--S(O).sub.j(CR.sup.4R.sup.5).sub.t(4 to 12 membered heterocyclic),
--S(O).sub.j(C.sub.1-C.sub.6 alkyl),
--(CR.sup.4R.sup.5).sub.t(C.sub.6-C.sub.10 aryl),
--(CR.sup.4R.sup.5).sub.pC(O)(CR.sup.4R.sup.5).sub.t(C.sub.6-C.sub.10
aryl),
--(CR.sup.4R.sup.5).sub.pO(CR.sup.4R.sup.5).sub.t(C.sub.6-C.sub.10
aryl), --NR.sup.4(CR.sup.4R.sup.5).sub.t(C.sub.6-C.sub.10 aryl),
--(CR.sup.4R.sup.5).sub.t(4 to 12 membered heterocyclic), and
--(CR.sup.4R.sup.5).sub.pC(O)(CR.sup.4R.sup.5).sub.t(4 to 12
membered heterocyclic), wherein each t is independently an integer
from 0 to 5, each p is independently an integer from 0 to 5, and
each j is an integer from 0 to 2; said alkyl, alkenyl and alkynyl
groups optionally contain 1 or 2 hetero moieties selected from O,
--S(O).sub.j-- wherein j is an integer from 0 to 2, and
--N(R.sup.3)-- with the proviso that two O atoms, two S atoms, or
an O and S atom are not attached directly to each other, and the
proviso that an O atom, a S atom or a N atom are not attached
directly to a triple bond or a non-aromatic double bond; said
cycloalkyl, aryl and heterocyclic R.sup.2 groups are optionally
fused to a C.sub.6-C.sub.10 aryl group, a C.sub.5-C.sub.8
cycloalkyl group, or a 4 to 12 membered heterocyclic group; and
said alkyl, alkenyl, alkynyl, aryl and heterocyclic moieties of the
foregoing R.sup.2 groups are optionally substituted by 1 to 5
substituents independently selected from halo, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,
--NR.sup.4SO.sub.2R.sup.6, --SO.sub.2NR.sup.3R.sup.4,
--C(O)R.sup.3, --C(O)OR.sup.3, --OC(O)R.sup.3,
--NR.sup.4C(O)OR.sup.6, --NR.sup.4C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --NR.sup.3R.sup.4, --OR.sup.3,
C.sub.1-C.sub.10 alkyl, --S(O).sub.j(C.sub.1-C.sub.6 alkyl),
--(CR.sup.4R.sup.5).sub.t(C.sub.6-C.sub.10 aryl), and
--(CR.sup.4R.sup.5).sub.t(4 to 12 membered heterocyclic), wherein
each t is independently an integer from 0 to 5 and each j is
independently an integer from 0 to 2; R.sup.1 is
--(CR.sup.4R.sup.5).sub.t(C.sub.6-C.sub.10 aryl) or
--(CR.sup.4R.sup.5).sub.t(4 to 12 membered heterocyclic) wherein t
is an integer from 0 to 5; and R.sup.1 is optionally substituted
with 1 to 5 R.sup.2 groups; each R.sup.3 is independently selected
from H, C.sub.1-C.sub.10 alkyl,
--(CR.sup.4R.sup.5).sub.t(C.sub.6-C.sub.10 aryl), and
--(CR.sup.4R.sup.5).sub.t(4 to 12 membered heterocyclic), wherein
each t is independently an integer from 0 to 5; said alkyl group
optionally includes 1 or 2 hetero moieties selected from O,
--S(O).sub.j-- wherein j is an integer ranging from 0 to 2, and
--N(R.sup.4)-- with the proviso that two O atoms, two S atoms, or
an O and S atom are not attached directly to each other; said
cycloalkyl, aryl and heterocyclic R.sup.3 groups are optionally
fused to a C.sub.6-C.sub.10 aryl group, a C.sub.5-C.sub.8
cycloalkyl group, or a 4 to 12 membered heterocyclic group; and
R.sup.3, except when H, is optionally substituted by 1 to 5
substituents independently selected from oxo, halo, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,
--C(O)R.sup.4, --C(O)OR.sup.4, --OC(O)R.sup.4,
--NR.sup.4C(O)R.sup.5, --C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5,
hydroxy, C.sub.1-C.sub.6 alkyl, trifluoromethyl, trifluoromethoxy,
and C.sub.1-C.sub.6 alkoxy, and with the proviso that R.sup.3 must
be attached through a carbon atom unless R.sup.3 is H; each R.sup.4
or R.sup.5 is independently H or C.sub.1-C.sub.6 alkyl; or where
R.sup.4 and R.sup.5 are attached to the same carbon atom, R.sup.4
and R.sup.5 may be taken together to form a C.sub.3-C.sub.10
cycloalkyl group; each R.sup.6 is independently selected from
C.sub.1-C.sub.10 alkyl, --(CR.sup.4R.sup.5).sub.t(C.sub.6-C.sub.10
aryl), and --(CR.sup.4R.sup.5).sub.t(4 to 12 membered
heterocyclic), wherein each t is independently an integer from 0 to
5; said alkyl group optionally includes 1 or 2 hetero moieties
selected from O, --S(O).sub.j-- wherein j is an integer ranging
from 0 to 2, and --N(R.sup.4)-- with the proviso that two O atoms,
two S atoms, or an O and S atom are not attached directly to each
other; said cycloalkyl, aryl and heterocyclic R.sup.6 groups are
optionally fused to a C.sub.6-C.sub.10 aryl group, a
C.sub.5-C.sub.8 cycloalkyl group, or a 4 to 12 membered
heterocyclic group; and R.sup.6 is optionally substituted by 1 to 5
substituents independently selected from oxo, halo, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,
--C(O)R.sup.4, --C(O)OR.sup.4, --OC(O)R.sup.4,
--NR.sup.4C(O)R.sup.5, --C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5,
hydroxy, C.sub.1-C.sub.6 alkyl, trifluoromethyl, trifluoromethoxy,
and C.sub.1-C.sub.6 alkoxy.
2. The compound according to claim 1 wherein the A moiety in
-A-X.sup.2 is selected from a direct bond, --C(O)NH--, --NHC(O)--,
--SO.sub.2NH--, --NHSO.sub.2--, --NHC(O)NH--, and --NHC(S)NH--.
3. The compound according to claim 1 selected from the group
consisting of: 3-(1H-Benzimidazol-1-yl)-3-(4-ethylphenyl)propanoic
acid;
3-Phenyl-3-[6-(trifluoromethyl)-1H-benzimidazol-1-yl]propanoic
acid; (3R)-3-(1H-Benzimidazol-1-yl)-3-phenylpropanoic acid;
(3S)-3-(1H-Benzimidazol-1-yl)-4-phenylbutanoic acid;
3-(1H-Benzimidazol-1-yl)-3-(4-chlorophenyl)propanoic acid;
3-Phenyl-3-(4-{4-[(1,4,5,6-tetrahydro-2-pyrimidinylamino)carbonyl]-1-pipe-
ridinyl}-1H-benzimidazol-1-yl)propanoic acid;
3-{5-[(3-Nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid;
3-{5-[(3-Aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoi-
c acid;
3-{5-[(3-{[Amino(imino)methyl]amino}benzoyl)amino]-1H-benzimidazol-
-1-yl}-3-phenylpropanoic acid;
3-{5-[(4-{[Amino(imino)methyl]amino}benzoyl)amino]-1H-benzimidazol-1-yl}--
3-phenylpropanoic acid;
3-{5-[(Anilinocarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid;
3-{5-[(2-Phenoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropan-
oic acid;
3-{5-[(2,6-Dimethoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-pheny-
lpropanoic acid;
3-Phenyl-3-[5-({[2-(phenylsulfanyl)-3-pyridinyl]carbonyl}amino)-1H-benzim-
idazol-1-yl]propanoic acid;
3-(5-{[(2-Phenoxy-3-pyridinyl)carbonyl]amino}-1H-benzimidazol-1-yl)-3-phe-
nylpropanoic acid;
3-{5-[(2-Hydroxy-5-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylprop-
anoic acid;
3-{6-[(2-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid;
3-(6-{[3-(1H-Indol-3-yl)propanoyl]amino}-1H-benzimidazol-1-yl)-3-ph-
enylpropanoic acid;
3-Phenyl-3-[6-({[2-(phenylsulfanyl)-3-pyridinyl]carbonyl}amino)-1H-benzim-
idazol-1-yl]propanoic acid;
3-{6-[(2-Bromo-5-methoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylprop-
anoic acid;
3-Phenyl-3-(6-{[(4-phenyl-1,2,3-thiadiazol-5-yl)carbonyl]amino}-1H-benzim-
idazol-1-yl)propanoic acid;
3-{6-[(3-Bromo-2,6-dimethoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenyl-
propanoic acid;
3-Phenyl-3-{6-[(2,3,5-trichloro-6-hydroxybenzoyl)amino]-1H-benzimidazol-1-
-yl}propanoic acid;
3-(5-Nitro-1H-benzimidazol-1-yl)-3-(3-pyridinyl)propanoic acid;
3-(5-Amino-1H-benzimidazol-1-yl)-3-(3-pyridinyl)propanoic acid;
3-{5-[(Phenylsulfonyl)amino]-1H-benzimidazol-1-yl}-3-(3-pyridinyl)propano-
ic acid; 3-(2-Naphthyl)-3-(5-nitro-1H-benzimidazol-1-yl)propanoic
acid; 3-(5-Amino-1H-benzimidazol-1-yl)-3-(2-naphthyl)propanoic
acid;
3-(2-Naphthyl)-3-{5-[(phenylsulfonyl)amino]-1H-benzimidazol-1-yl}propanoi-
c acid;
3-(5-Amino-1H-benzimidazol-1-yl)-3-(4-methoxyphenyl)propanoic acid;
3-(4-Methoxyphenyl)-3-{5-[(phenylsulfonyl)amino]-1H-benzimidazol-1--
yl}propanoic acid;
1-(2-Carboxy-1-phenylethyl)-1H-benzimidazole-5-carboxylic acid;
3-[5-(Anilinocarbonyl)-1H-benzimidazol-1-yl]-3-phenylpropanoic
acid; and
3-Phenyl-3-(5-{[4-(2-pyrazinyl)-1-piperazinyl]carbonyl}-1H-benzimidazol-1-
-yl)propanoic acid; or a pharmaceutically acceptable salt
thereof.
4. A compound selected from: TABLE-US-00005
3-phenyl-3-{5-[(2-quinolinylcarbonyl)amino]-1H-benzimidazol-1-yl}propanoic
acid
3-{5-[(3-isoquinolinylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropan-
oic acid
3-phenyl-3-{5-[(2-quinoxalinylcarbonyl)amino]-1H-benzimidazol-1-yl}propano-
ic acid
3-{5-[(1-isoquinolinylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropan-
oic acid
3-{5-[(2,3-dihydro-1H-indol-2-ylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-
phenylpropanoic acid
3-phenyl-3-{5-[(2-quinoxalinylcarbonyl)amino]-1H-benzimidazol-1-yl}propano-
ic acid
3-phenyl-3-{5-[(2-pyrazinylcarbonyl)amino]-1H-benzimidazol-1-yl}propanoic
acid
3-phenyl-3-{5-[(3-pyridinylcarbonyl)amino]-1H-benzimidazol-1-yl}propanoic
acid
3-[5-(isonicotinoylamino)-1H-benzimidazol-1-yl]-3-phenylpropanoic
acid
3-(5-{[(2-hydroxy-3-pyridinyl)carbonyl]amino}-1H-benzimidazol-1-yl)-3-phen-
ylpropanoic acid
3-{5-[(1H-indol-2-ylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoi-
c acid
3-{5-[(1H-indol-3-ylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoi-
c acid
3-{5-[(3-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-phenyl-3-{5-[(3-pyridinylacetyl)amino]-1H-benzimidazol-1-yl}propanoic
acid
3-{5-[(1H-imidazol-4-ylacetyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropano-
ic acid
3-(5-{[(2E)-3-(3-nitrophenyl)-2-propenoyl]amino}-1H-benzimidazol-1-yl)-3-
phenylpropanoic acid
3-(5-{[3-(1H-benzimidazol-2-yl)propanoyl]amino}-1H-benzimidazol-1-yl)-3-
phenylpropanoic acid
3-phenyl-3-(5-{[3-(3,4,5-trimethoxyphenyl)propanoyl]amino}-1H-benzimidazol-
-1- yl)propanoic acid
3-{5-[(1H-indol-3-ylacetyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-(5-{[3-(1H-indol-3-yl)propanoyl]amino}-1H-benzimidazol-1-yl)-3-phenylpro-
panoic acid
3-phenyl-3-{5-[(2-pyridinylcarbonyl)amino]-1H-benzimidazol-1-yl}propanoic
acid
3-(5-{[4-(1H-indol-3-yl)butanoyl]amino}-1H-benzimidazol-1-yl)-3-phenylprop-
anoic acid
3-(5-{[(5-methyl-2-pyrazinyl)carbonyl]amino}-1H-benzimidazol-1-yl)-3-pheny-
lpropanoic acid
3-(5-{[(5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)carbonyl]amino}-1H-benzimi-
dazol-1-yl)- 3-phenylpropanoic acid
3-(5-{[(4-oxo-4,5,6,7-tetrahydro-1-benzofuran-3-yl)carbonyl]amino}-1H-benz-
imidazol-1- yl)-3-phenylpropanoic acid
3-[5-({[2-(methylsulfanyl)-3-pyridinyl]carbonyl}amino)-1H-benzimidazol-1-y-
l]-3- phenylpropanoic acid
3-[5-({[3-chloro-4-(isopropylsulfonyl)-2-thienyl]carbonyl}amino)-1H-benzim-
idazol-1-yl]- 3-phenylpropanoic acid
3-(5-{[(6-oxo-1,4,5,6-tetrahydro-3-pyridazinyl)carbonyl]amino}-1H-benzimid-
azol-1-yl)-3- phenylpropanoic acid
3-[5-({[2-(2,3-dihydro-1,4-benzodioxin-2-yl)-1,3-thiazol-4-yl]carbonyl}ami-
no)-1H- benzimidazol-1-yl]-3-phenylpropanoic acid
3-[5-({(2E)-3-[3-nitro-4-(1-pyrrolidinyl)phenyl]-2-propenoyl}amino)-1H-ben-
zimidazol-1- yl]-3-phenylpropanoic acid
3-(5-{[3-(2-oxocyclododecyl)propanoyl]amino}-1H-benzimidazol-1-yl)-3-pheny-
lpropanoic acid
3-(5-{[(1-tert-butyl-3-methyl-1H-pyrazol-5-yl)carbonyl]amino}-1H-benzimida-
zol-1-yl)-3- phenylpropanoic acid
3-(5-{[(2Z)-2-(3-oxo-2-benzofuran-1(3H)-ylidene)ethanoyl]amino}-1H-benzimi-
dazol-1- yl)-3-phenylpropanoic acid
3-{5-[(1-benzothien-2-ylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylprop-
anoic acid
3-phenyl-3-(5-{[4-(trifluoromethoxy)benzoyl]amino}-1H-benzimidazol-1-yl)pr-
opanoic acid
3-(5-{[(5-chloro-2-hydroxy-3-pyridinyl)carbonyl]amino}-1H-benzimidazol-1-y-
l)-3- phenylpropanoic acid
3-(5-{[(2E)-4-oxo-4-(2,3,4,5,6-pentamethylphenyl)-2-butenoyl]amino}-1H-ben-
zimidazol- 1-yl)-3-phenylpropanoic acid
3-(5-{[(6-bromo-2-oxo-2H-chromen-3-yl)carbonyl]amino}-1H-benzimidazol-1-yl-
)-3- phenylpropanoic acid
3-phenyl-3-(5-{[4-(trifluoroacetyl)benzoyl]amino}-1H-benzimidazol-1yl)prop-
anoic acid
3-[5-({[(4-chlorobenzoyl)amino]acetyl}amino)-1H-benzimidazol-1-yl]-3-pheny-
lpropanoic acid
3-(5-{[(2,7-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)carbonyl]amino}-1H-benzi-
midazol-1- yl)-3-phenylpropanoic acid
3-(5-{[(4-acetyl-5-methyl-2-oxo-2,3-dihydro-1H-pyrrol-3-yl)acetyl]amino}-1-
H- benzimidazol-1-yl)-3-phenylpropanoic acid
3-phenyl-3-(5-{[(4-phenyl-1,2,3-thiadiazol-5-yl)carbonyl]amino}-1H-benzimi-
dazol-1- yl)propanoic acid
3-[5-({[1-(4-chlorobenzyl)-5-oxo-3-pyrrolidinyl]carbonyl}amino)-1H-benzimi-
dazol-1-yl]- 3-phenylpropanoic acid
3-(5-{[({[(Z)-1-(4-chlorophenyl)ethylidene]amino}oxy)acetyl]amino}-1H-benz-
imidazol-1- yl)-3-phenylpropanoic acid
3-phenyl-3-{5-[(1,2,3-thiadiazol-4-ylcarbonyl)amino]-1H-benzimidazol-1-yl}-
propanoic acid
3-(5-{[(5-chloro-1-benzothien-3-yl)acetyl]amino}-1H-benzimidazol-1-yl)-3-
phenylpropanoic acid
3-[5-({[5-chloro-2-(methylsulfanyl)-4-pyrimidinyl]carbonyl}amino)-1H-benzi-
midazol-1- yl]-3-phenylpropanoic acid
3-[5-({[1-(2-furylmethyl)-5-oxo-3-pyrrolidinyl]carbonyl}amino)-1H-benzimid-
azol-1-yl]-3- phenylpropanoic acid
3-(5-{[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)carbonyl]amino}-1H-benzimida-
zol-1-yl)-3- phenylpropanoic acid
3-(5-{[(5-oxo-2-pyrrolidinyl)carbonyl]amino}-1H-benzimidazol-1-yl)-3-pheny-
lpropanoic acid
3-(5-{[(2,5-dimethoxyphenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpr-
opanoic acid
3-[5-({[2-(4-methylphenoxy)-3-pyridinyl]carbonyl}amino)-1H-benzimidazol-1--
yl]-3- phenylpropanoic acid
3-[5-(2-methyl-6-nitro-4-oxo-3(4H)-quinazolinyl)-1H-benzimidazol-1-yl]-3-
phenylpropanoic acid
3-(5-{[(3-methoxyphenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropan-
oic acid
3-(5-{[(4-methoxyphenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropan-
oic acid
3-(5-{[(2-methoxyphenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropan-
oic acid
3-(5-{[(2-phenoxy-3-pyridinyl)carbonyl]amino}-1H-benzimidazol-1-yl)-3-phen-
ylpropanoic acid
3-[5-({2-[4-(aminocarbonyl)phenoxy]-2-methylpropanoyl}amino)-1H-benzimidaz-
ol-1-yl]- 3-phenylpropanoic acid
3-phenyl-3-{5-[(1,2,3,4-tetrahydro-2-naphthalenylcarbonyl)amino]-1H-benzim-
idazol-1- yl}propanoic acid
3-(5-{[(3,5-dimethyl-4-isoxazolyl)carbonyl]amino}-1H-benzimidazol-1-yl)-3--
phenylpropanoic acid
3-phenyl-3-{5-[(1H-pyrrol-2-ylcarbonyl)amino]-1H-benzimidazol-1-yl}propano-
ic acid
3-[5-({[(2S)-5-oxopyrrolidinyl]carbonyl}amino)-1H-benzimidazol-1-yl]-3-phe-
nylpropanoic acid
3-phenyl-3-[5-({[(3S,4R,5S)-3,4,5-trihydroxy-1-cyclohexen-1-yl]carbonyl}am-
ino)-1H- benzimidazol-1-yl]propanoic acid
3-{5-[(cyclohexylacetyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-phenyl-3-(5-{[4-(1H-pyrrol-1-yl)benzoyl]amino}-1H-benzimidazol-1-yl)prop-
anoic acid
3-(5-{[(2,4-dihydroxy-5-pyrimidinyl)carbonyl]amino}-1H-benzimidazol-1-yl)--
3- phenylpropanoic acid
3-(5-{[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl]amino}-1H-benzi-
midazol-1- yl)-3-phenylpropanoic acid
3-(5-{[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl]amino}-1H-benzi-
midazol-1- yl)-3-phenylpropanoic acid
3-[5-({[1-(4-chlorophenyl)cyclopentyl]carbonyl}amino)-1H-benzimidazol-1-yl-
]-3- phenylpropanoic acid
3-(5-{[(4-oxo-2-thioxo-1,3-thiazolidin-3-yl)acetyl]amino}-1H-benzimidazol--
1-yl)-3- phenylpropanoic acid
3-{5-[([1,1'-biphenyl]-4-ylacetyl)amino]-1H-benzimidazol-1-yl}-3-phenylpro-
panoic acid
3-(5-{[(6-methoxy-3-oxo-2,3-dihydro-1H-inden-1-yl)acetyl]amino}-1H-benzimi-
dazol-1- yl)-3-phenylpropanoic acid
3-{5-[(9H-fluoren-9-ylacetyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoi-
c acid
3-(5-{[(9-oxo-9H-fluoren-1-yl)carbonyl]amino}-1H-benzimidazol-1-yl)-3-phen-
ylpropanoic acid
3-(5-{[(2-nitrophenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropanoi-
c acid
3-(5-{[(4-nitrophenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropanoi-
c acid
3-{5-[(9-anthrylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-(5-{[(2-methylphenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropano-
ic acid
3-(5-{[(2,6-dioxo-1,2,3,6-tetrahydro-4-pyrimidinyl)carbonyl]amino}-1H-benz-
imidazol-1- yl)-3-phenylpropanoic acid
3-(5-{[(4-methylphenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropano-
ic acid
3-{5-[(3-methylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-phenyl-3-{5-[(4-vinylbenzoyl)amino]-1H-benzimidazol-1-yl}propanoic
acid
3-{5-[(4-methylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{5-[(2-methylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-(5-{[(3-methylphenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropano-
ic acid
3-(5-{[(3-nitrophenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropanoi-
c acid
3-{5-[(4-bromobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-phenyl-3-{5-[(9H-xanthen-9-ylcarbonyl)amino]-1H-benzimidazol-1-yl}propan-
oic acid
3-{5-[(2-phenoxypropanoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-(5-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]amino}-1H-benzimidaz-
ol-1-yl)-3- phenylpropanoic acid
3-{5-[(1,3-benzodioxol-5-ylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylp-
ropanoic acid
3-phenyl-3-{5-[(phenylacetyl)amino]-1H-benzimidazol-1-yl}propanoic
acid
3-{5-[(bicyclo[2.2.1]hept-5-en-2-ylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-
- phenylpropanoic acid
3-(5-{[hydroxy(phenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropanoi-
c acid
3-(5-{[(2-naphthyloxy)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropanoi-
c acid
3-phenyl-3-(5-{[(1-phenylcyclopentyl)carbonyl]amino}-1H-benzimidazol-1-yl)-
propanoic acid
3-phenyl-3-{5-[(2-sulfanylbenzoyl)amino]-1H-benzimidazol-1-yl}propanoic
acid
3-(5-{[cyclopentyl(phenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylprop-
anoic acid
3-{5-[(4-tert-butylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{5-[(1-adamantylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{5-[(4-methoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{5-[(4-cyclohexylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-[5-(1-naphthoylamino)-1H-benzimidazol-1-yl]-3-phenylpropanoic
acid 3-[5-(benzoylamino)-1H-benzimidazol-1-yl]-3-phenylpropanoic
acid
3-(5-{[(2E)-3-(4-bromophenyl)-2-propenoyl]amino}-1H-benzimidazol-1-yl)-3-
phenylpropanoic acid
3-{5-[(3-bromo-4-methoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropa-
noic acid
3-{5-[(4-butylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-(5-{[4-(dimethylamino)benzoyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropa-
noic acid
3-(5-{[(4-bromo-1-ethyl-3-methyl-1H-pyrazol-5-yl)carbonyl]amino}-1H-benzim-
idazol-1- yl)-3-phenylpropanoic acid
3-{5-[(4-nitorbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-(5-{[(2-cyclopropyl-4-quinolinyl)carbonyl]amino}-1H-benzimidazol-1-yl)-3-
- phenylpropanoic acid
3-phenyl-3-[5-({[2-(2-thienyl)-4-quinolinyl]carbonyl}amino)-1H-benzimidazo-
l-1- yl]propanoic acid
3-{5-[(3,5-dinitrobenzyol)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-phenyl-3-{5-[(3-phenyl-2-propynol)amino]-1H-benzimidazol-1-yl}propanoic
acid
3-{5-[(4-fluoro-1-naphthoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-(5-{[(7-methyl-2-phenyl-4-quinolinyl)carbonyl]amino}-1H-benzimidazol-1-y-
l)-3- phenylpropanoic acid
3-(5-{[(5-bromo-4-methoxy-3-thienyl)carbonyl]amino}-1H-benzimidazol-1-yl)--
3- phenylpropanoic acid
3-{5-[(4-[1,1'-biphenyl]-4-yl-4-oxobutanoyl)amino]-1H-benzimidazol-1-yl}-3-
- phenylpropanoic acid
3-{5-[(1-cyclohexen-1-ylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylprop-
anoic acid
3-(5-{[(4-bromophenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropanoi-
c acid
3-(5-{[2-(methylsulfanyl)benzoyl]amino}-1H-benzimidazol-1-yl)-3-phenylprop-
anoic acid
3-(5-{[(2E)-3-(5-bromo-2-ethoxyphenyl)-2-propenoyl]amino}-1H-benzimidazol--
1-yl)-3- phenylpropanoic acid
3-(5-{[4-(methylsulfonyl)benzoyl]amino}-1H-benzimidazol-1-yl)-3-phenylprop-
anoic acid
3-(5-{[2-nitro-4-(trifluoromethyl)benzoyl]amino}-1H-benzimidazol-1-yl)-3-
phenylpropanoic acid
3-{5-[([1,1'-biphenyl]-4-ylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylp-
ropanoic acid
3-{5-[(4-benzoylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-phenyl-3-(5-{[4-(trifluoromethyl)benzoyl]amino}-1H-benzimidazol-1-yl)pro-
panoic acid
3-{5-[(4-acetylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{5-[(4-cyanobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-(5-{[2,4-bis(trifluoromethyl)benzoyl]amino}-1H-benzimidazol-1-yl)-3-phen-
ylpropanoic acid
3-phenyl-3-(5-{[3-(trifluoromethyl)benzoyl]amino}-1H-benzimidazol-1-yl)pro-
panoic acid
3-{5-[(3-cyanobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{5-[(1H-benzimidazol-5-ylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylp-
ropanoic acid
3-{5-[(diphenylacetyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{5-[(2-hydroxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{5-[(4-ethylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{5-[(3-bromo-2,6-dimethoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylp-
ropanoic acid
3-{5-[(4-bromo-2,3,5,6-tetrafluorobenzoyl)amino]-1H-benzimidazol-1-yl}-3-
phenylpropanoic acid
3-{5-[(5-bromo-2-furoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{5-[(3-iodobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{5-[(2-formylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{5-[(2-bromobenzoyl)amino]-1H-benzimidazol-1-yl-}-3-phenylpropanoic
acid
3-{5-[(3-bromobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-(5-{[(5-bromo-3-pyridinyl)carbonyl]amino}-1H-benzimidazol-1-yl)-3-phenyl-
propanoic acid
3-(5-{[(5-bromo-2-thienyl)carbonyl]amino}-1H-benzimidazol-1-yl)-3-phenylpr-
opanoic acid
3-{5-[(2-bromo-5-methoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenlpropan-
oic acid
3-{5-[(4-bromo-2-methylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropan-
oic acid
3-{5-[(4-bromo-2-chlorobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropan-
oic acid
3-(5-{[(2E)-3-(3-bromo-4-fluorophenyl)-2-propenoyl]amino}-1H-benzimidazol--
1-yl)-3- phenylpropanoic acid
3-(5-{[(2E)-3-(6-bromo-1,3-benzodioxol-5-yl)-2-propenoyl]amino}-1H-benzimi-
dazol-1- yl)-3-phenylpropanoic acid
3-phenyl-3-[5-({[2-(phenylsulfanyl)-3-pyridinyl]carbonyl}amino)-1H-benzimi-
dazol-1- yl]propanoic acid
3-{5-[(2-hydroxy-5-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropa-
noic acid
3-{5-[(2-hydroxy-3-methoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpro-
panoic acid
3-(5-{[(4-hydroxy-3-methoxyphenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-
phenylpropanoic acid
3-{5-[(2,5-dihydroxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{5-[(2-hydroxy-3-methylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylprop-
anoic acid
3-{5-[(3-hydroxy-4-methylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylprop-
anoic acid
3-(5-{[(3-hydroxy-4-methoxyphenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-
phenylpropanoic acid
3-(5-{[(4,7-dimethylpyrazolo[5,1-c][1,2,4]triazin-3-yl)carbonyl]amino}-1H--
benzimidazol- 1-yl)-3-phenylpropanoic acid
3-(5-{[3-(2,4-dihydroxyphenyl)propanoyl]amino}-1H-benzimidazol-1-yl)-3-
phenylpropanoic acid
3-(5-{[(3,5-ditert-butyl-4-hydroxyphenyl)acetyl]amino}-1H-benzimidazol-1-y-
l)-3- phenylpropanoic acid
3-(5-{[(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl)carbonyl-
]amino}-1H- benzimidazol-1-yl)-3-phenylpropanoic acid
3-{5-[(3,5-dichloro-2-hydroxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenyl-
propanoic acid
3-phenyl-3-{5-[(2,4,6-trihydroxybenzoyl)amino]-1H-benzimidazol-1-yl}propan-
oic acid
3-{5-[(2-hydroxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-phenyl-3-{5-[(2,3,5-trichloro-6-hydroxybenzoyl)amino]-1H-benzimidazol-1--
yl}propanoic acid
3-{5-[(5-chloro-2-hydroxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylprop-
anoic acid
3-{5-[(5-bromo-2-hydroxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropa-
noic acid
3-{5-[(2-hydroxy-4-methylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylprop-
anoic acid
3-(5-{[(3,4-dihydroxyphenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpr-
opanoic acid
3-{5-[(2-fluoro-6-iodobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropano-
ic acid
3-phenyl-3-{6-[(2-quinolinylcarbonyl)amino]-1H-benzimidazol-1-yl}propanoic
acid
3-{6-[(3-isoquinolinylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropan-
oic acid
3-phenyl-3-{6-[(2-quinoxalinylcarbonyl)amino]-1H-benzimidazol-1-yl}propano-
ic acid
3-{6-[(1-isoquinolinylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropan-
oic acid
3-{6-[(2,3-dihydro-1H-indol-2-ylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-
phenylpropanoic acid
3-phenyl-3-{6-[(2-quinoxalinylcarbonyl)amino]-1H-benzimidazol-1-yl}propano-
ic acid
3-phenyl-3-{6-[(2-pyrazinylcarbonyl)amino]-1H-benzimidazol-1-yl}propanoic
acid
3-phenyl-3-{6-[(3-pyridinylcarbonyl)amino]-1H-benzimidazol-1-yl}propanoic
acid
3-[6-(isonicotinoylamino)-1H-benzimidazol-1-yl]-3-phenylpropanoic
acid
3-(6-{[(2-hydroxy-3-pyridinyl)carbonyl]amino}-1H-benzimidazol-1-yl)-3-phen-
ylpropanoic acid
3-{6-[(1H-indol-2-ylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoi-
c acid
3-{6-[(1H-indol-3-ylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoi-
c acid
3-{6-[(3-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-(6-{[(2E)-3-(1H-indol-3-yl)-2-propenoyl]amino}-1H-benzimidazol-1-yl)-3-
phenylpropanoic acid
3-(6-{[(2E)-3-(3-nitrophenyl)-2-propenoyl]amino}-1H-benzimidazol-1-yl)-3-
phenylpropanoic acid
3-(6-{[3-(1H-benzimidazol-2-yl)propanoyl]amino}-1H-benzimidazol-1-yl)-3-
phenylpropanoic acid
3-phenyl-3-(6-{[3-(3,4,5-trimethoxyphenyl)propanoyl]amino}-1H-benzimidazol-
-1- yl)propanoic acid
3-{6-[(1H-indol-3-ylacetyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-(6-{[3-(1H-indol-3-yl)propanoyl]amino}-1H-benzimidazol-1-yl)-3-phenylpro-
panoic acid
3-phenyl-3-{6-[(2-pyridinylcarbonyl)amino]-1H-benzimidazol-1-yl}propanoic
acid
3-(6-{[(5-methyl-2-pyrazinyl)carbonyl]amino}-1H-benzimidazol-1-yl)-3-pheny-
lpropanoic acid
3-(6-{[(5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)carbonyl]amino}-1H-benzimi-
dazol-1-yl)- 3-phenylpropanoic acid
3-(6-{[(4-oxo-4,5,6,7-tetrahydro-1-benzofuran-3-yl)carbonyl]amino}-1H-benz-
imidazol-1- yl)-3-phenylpropanoic acid
3-[6-({[2-(methylsulfanyl)-3-pyridinyl]carbonyl}amino)-1H-benzimidazol-1-y-
l]-3- phenylpropanoic acid
3-[6-({[3-chloro-4-(isopropylsulfonyl)-2-thienyl]carbonyl}amino)-1H-benzim-
idazol-1-yl]- 3-phenylpropanoic acid
3-(6-{[(6-oxo-1,4,5,6-tetrahydro-3-pyridazinyl)carbonyl]amino}-1H-benzimid-
azol-1-yl)-3- phenylpropanoic acid
3-[6-({[2-(2,3-dihydro-1,4-benzodioxin-2-yl)-1,3-thiazol-4-yl]carbonyl}ami-
no)-1H- benzimidazol-1-yl]-3-phenylpropanoic acid
3-[6-({(2E)-3-[3-nitro-4-(1-pyrrolidinyl)phenyl]-2-propenoyl}amino)-1H-ben-
zimidazol-1- yl]-3-phenylpropanoic acid
3-(6-{[3-(2-oxocyclododecyl)propanoyl]amino}-1H-benzimidazol-1-yl)-3-pheny-
lpropanoic acid
3-(6-{[(1-tert-butyl-3-methyl-1H-pyrazol-5-yl)carbonyl]amino}-1H-benzimida-
zol-1-yl)-3- phenylpropanoic acid
3-(6-{[(2Z)-2-(3-oxo-2-benzofuran-1(3H)-ylidene)ethanoyl]amino}-1H-benzimi-
dazol-1- yl)-3-phenylpropanoic acid
3-{6-[(1-benzothien-2-ylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylprop-
anoic acid
3-phenyl-3-(6-{[4-(trifluoromethoxy)benzoyl]amino}-1H-benzimidazol-1-yl)pr-
opanoic acid
3-(6-{[(5-chloro-2-hydroxy-3-pyridinyl)carbonyl]amino}-1H-benzimidazol-1-y-
l)-3- phenylpropanoic acid
3-(6-{[(2E)-4-oxo-4-(2,3,4,5,6-pentamethylphenyl)-2-butenoyl]amino}-1H-ben-
zimidazol- 1-yl)-3-phenylpropanoic acid
3-(6-{[(6-bromo-2-oxo-2H-chromen-3-yl)carbonyl]amino}-1H-benzimidazol-1-yl-
)-3- phenylpropanoic acid
3-phenyl-3-(6-{[4-(trifluoroacetyl)benzoyl]amino}-1H-benzimidazol-1-yl)pro-
panoic acid
3-[6-({[(4-chlorobenzoyl)amino]acetyl}amino)-1H-benzimidazol-1-yl]-3-pheny-
lpropanoic acid
3-(6-{[(2,7-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)carbonyl]amino}-1H-benzi-
midazol-1- yl)-3-phenylpropanoic acid
3-(6-{[2-(4-aminophenoxy)-2-methylpropanoyl]amino}-1H-benzimidazol-1-yl)-3-
- phenylpropanoic acid
3-(6-{[(4-acetyl-5-methyl-2-oxo-2,3-dihydro-1H-pyrrol-3-yl)acetyl]amino}-1-
H- benzimidazol-1-yl)-3-phenylpropanoic acid
3-phenyl-3-(6-{[(4-phenyl-1,2,3-thiadiazol-5-yl)carbonyl]amino}-1H-benzimi-
dazol-1- yl)propanoic acid
3-[6-({[1-(4-chlorobenzyl)-5-oxo-3-pyrrolidinyl]carbonyl}amino)-1H-benzimi-
dazol-1-yl]- 3-phenylpropanoic acid
3-(6-{[({[(Z)-1-(4-chlorophenyl)ethylidene]amino}oxy)acetyl]amino}-1H-benz-
imidazol-1- yl)-3-phenylpropanoic acid
3-phenyl-3-{6-[(1,2,3-thiadiazol-4-ylcarbonyl)amino]-1H-benzimidazol-1-yl}-
propanoic acid
3-(6-{[(5-chloro-1-benzothien-3-yl)acetyl]amino}-1H-benzimidazol-1-yl)-3-
phenylpropanoic acid
3-[6-({[5-chloro-2-(methylsulfanyl)-4-pyrimidinyl]carbonyl}amino)-1H-benzi-
midazol-1- yl]-3-phenylpropanoic acid
3-[6-({[1-(2-furylmethyl)-5-oxo-3-pyrrolidinyl]carbonyl}amino)-1H-benzimid-
azol-1-yl]-3- phenylpropanoic acid
3-(6-{[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)carbonyl]amino}-1H-benzimida-
zol-1-yl)-3- phenylpropanoic acid
3-(6-{[(5-oxo-2-pyrrolidinyl)carbonyl]amino}-1H-benzimidazol-1-yl)-3-pheny-
lpropanoic acid
3-(6-{[(2,5-dimethoxyphenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpr-
opanoic acid
3-[6-({[2-(4-methylphenoxy)-3-pyridinyl]carbonyl}amino)-1H-benzimidazol-1--
yl]-3- phenylpropanoic acid
3-[6-(2-methyl-6-nitro-4-oxo-3(4H)-quinazolinyl)-1H-benzimidazol-1-yl]-3-
phenylpropanoic acid
3-(6-{[(3-methoxyphenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropan-
oic acid
3-(6-{[(4-methoxyphenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropan-
oic acid
3-(6-{[(2-methoxyphenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropan-
oic acid
3-(6-{[(2-phenoxy-3-pyridinyl)carbonyl]amino}-1H-benzimidazol-1-yl)-3-phen-
ylpropanoic acid
3-[6-({2-[4-(aminocarbonyl)phenoxy]-2-methylpropanoyl}amino)-1H-benzimidaz-
ol-1-yl]- 3-phenylpropanoic acid
3-phenyl-3-{6-[(1,2,3,4-tetrahydro-2-naphthalenylcarbonyl)amino]-1H-benzim-
idazol-1- yl}propanoic acid
3-(6-{[(3,5-dimethyl-4-isoxazolyl)carbonyl]amino}-1H-benzimidazol-1-yl)-3--
phenylpropanoic acid
3-phenyl-3-{6-[(1H-pyrrol-2-ylcarbonyl)amino]-1H-benzimidazol-1-yl}propano-
ic acid
3-[6-({[(2S)-5-oxopyrrolidinyl]carbonyl}amino)-1H-benzimidazol-1-yl]-3-phe-
nylpropanoic acid
3-phenyl-3-[6-({[(3S,4R,5S)-3,4,5-trihydroxy-1-cyclohexen-1-yl]carbonyl}am-
ino)-1H- benzimidazol-1-yl]propanoic acid
3-{6-[(cyclohexylacetyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-phenyl-3-(6-{[4-(1H-pyrrol-1-yl)benzoyl]amino}-1H-benzimidazol-1-yl)prop-
anoic acid
3-(6-{[(2,4-dihydroxy-5-pyrimidinyl)carbonyl]amino}-1H-benzimidazol-1-yl)--
3- phenylpropanoic acid
3-(6-{[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl]amino}-1H-benzi-
midazol-1- yl)-3-phenylpropanoic acid
3-(6-{[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl]amino}-1H-benzi-
midazol-1- yl)-3-phenylpropanoic acid
3-[6-({[1-(4-chlorophenyl)cyclopentyl]carbonyl}amino)-1H-benzimidazol-1-yl-
]-3- phenylpropanoic acid
3-(6-{[(4-oxo-2-thioxo-1,3-thiazolidin-3-yl)acetyl]amino}-1H-benzimidazol--
1-yl)-3- phenylpropanoic acid
3-[6-({[(4S)-2,6-dioxohexahydro-4-pyrimidinyl]carbonyl}amino)-1H-benzimida-
zol-1-yl]- 3-phenylpropanoic acid
3-{6-[([1,1'-biphenyl]-4-ylacetyl)amino]-1H-benzimidazol-1-yl}-3-phenylpro-
panoic acid
3-(6-{[(6-methoxy-3-oxo-2,3-dihydro-1H-inden-1-yl)acetyl]amino}-1H-benzimi-
dazol-1- yl)-3-phenylpropanoic acid
3-{6-[(9H-fluoren-9-ylacetyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoi-
c acid
3-(6-{[(9-oxo-9H-fluoren-1-yl)carbonyl]amino}-1H-benzimidazol-1-yl)-3-phen-
ylpropanoic acid
3-(6-{[(2-nitrophenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropanoi-
c acid
3-(6-{[(4-nitrophenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropanoi-
c acid
3-{6-[(9-anthrylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-(6-{[(2-methylphenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropano-
ic acid
3-(6-{[(2,6-dioxo-1,2,3,6-tetrahydro-4-pyrimidinyl)carbonyl]amino}-1H-benz-
imidazol-1- yl)-3-phenylpropanoic acid
3-(6-{[(4-methylphenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropano-
ic acid
3-{6-[(3-methylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-phenyl-3-{6-[(4-vinylbenzoyl)amino]-1H-benzimidazol-1-yl}propanoic
acid
3-{6-[(4-methylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{6-[(2-methylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-(6-{[(3-methylphenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropano-
ic acid
3-(6-{[(3-nitrophenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropanoi-
c acid
3-{6-[(4-bromobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-phenyl-3-{6-[(9H-xanthen-9-ylcarbonyl)amino]-1H-benzimidazol-1-yl}propan-
oic acid
3-{6-[(2-phenoxypropanoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-(6-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]amino}-1H-benzimidaz-
ol-1-yl)-3- phenylpropanoic acid
3-{6-[(1,3-benzodioxol-5-ylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylp-
ropanoic acid
3-phenyl-3-{6-[(phenylacetyl)amino]-1H-benzimidazol-1-yl}propanoic
acid
3-{6-[(bicyclo[2.2.1]hept-5-en-2-ylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-
- phenylpropanoic acid
3-(6-{[hydroxy(phenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropanoi-
c acid
3-(6-{[(2-naphthyloxy)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropanoi-
c acid
3-phenyl-3-(6-{[(1-phenylcyclopentyl)carbonyl]amino}-1H-benzimidazol-1-yl)-
propanoic acid
3-phenyl-3-{6-[(tetrahydro-2-furanylcarbonyl)amino]-1H-benzimidazol-1-yl}p-
ropanoic acid
3-(6-{[cyclopentyl(phenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylprop-
anoic acid
3-{6-[(4-tert-butylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{6-[(1-adamantylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{6-[(4-methoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{6-[(4-cyclohexylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-[6-(1-naphthoylamino)-1H-benzimidazol-1-yl]-3-phenylpropanoic
acid 3-[6-(benzoylamino)-1H-benzimidazol-1-yl]-3-phenylpropanoic
acid
3-{6-[(5-isoxazolylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-(6-{[(2E)-3-(4-bromophenyl)-2-propenoyl]amino}-1H-benzimidazol-1-yl)-3-
phenylpropanoic acid
3-{6-[(3-bromo-4-methoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropa-
noic acid
3-{6-[(4-butylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-(6-{[4-(dimethylamino)benzoyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropa-
noic acid
3-(6-{[(4-bromo-1-ethyl-3-methyl-1H-pyrazol-5-yl)carbonyl]amino}-1H-benzim-
idazol-1- yl)-3-phenylpropanoic acid
3-{6-[(4-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-(6-{[(2-cyclopropyl-4-quinolinyl)carbonyl]amino}-1H-benzimidazol-1-yl)-3-
- phenylpropanoic acid
3-phenyl-3-[6-({[2-(2-thienyl)-4-quinolinyl]carbonyl}amino)-1H-benzimidazo-
l-1- yl]propanoic acid
3-{6-[(3,5-dinitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-phenyl-3-{6-[(3-phenyl-2-propynoyl)amino]-1H-benzimidazol-1-yl}propanoic
acid
3-{6-[(4-fluoro-1-naphthoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-(6-{[(acetylamino)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropanoic
acid
3-(6-{[(7-methyl-2-phenyl-4-quinolinyl)carbonyl]amino}-1H-benzimidazol-1-y-
l)-3- phenylpropanoic acid
3-(6-{[(5-bromo-4-methoxy-3-thienyl)carbonyl]amino}-1H-benzimidazol-1-yl)--
3- phenylpropanoic acid
3-{6-[(4-[1,1'-biphenyl]-4-yl-4-oxobutanoyl)amino]-1H-benzimidazol-1-yl}-3-
- phenylpropanoic acid
3-{6-[(1-cyclohexen-1-ylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylprop-
anoic acid
3-(6-{[(4-bromophenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpropanoi-
c acid
3-(6-{[2-(methylsulfanyl)benzoyl]amino}-1H-benzimidazol-1-yl)-3-phenylprop-
anoic acid
3-(6-{[(2E)-3-(5-bromo-2-ethoxyphenyl)-2-propenoyl]amino}-1H-benzimidazol--
1-yl)-3- phenylpropanoic acid
3-(6-{[4-(methylsulfonyl)benzoyl]amino}-1H-benzimidazol-1-yl)-3-phenylprop-
anoic acid
3-(6-{[2-nitro-4-(trifluoromethyl)benzoyl]amino}-1H-benzimidazol-1-yl)-3-
phenylpropanoic acid
3-{6-[([1,1'-biphenyl]-4-ylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylp-
ropanoic acid
3-{6-[(4-benzoylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-phenyl-3-(6-{[4-(trifluoromethyl)benzoyl]amino}-1H-benzimidazol-1-yl)pro-
panoic acid
3-{6-[(4-acetylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{6-[(4-cyanobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-(6-{[2,4-bis(trifluoromethyl)benzoyl]amino}-1H-benzimidazol-1-yl)-3-phen-
ylpropanoic acid
3-phenyl-3-(6-{[3-(trifluoromethyl)benzoyl]amino}-1H-benzimidazol-1-yl)pro-
panoic acid
3-{6-[(3-cyanobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-(6-{[4-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzoyl]amino}-1H-ben-
zimidazol- 1-yl)-3-phenylpropanoic acid
3-{6-[(1H-benzimidazol-5-ylcarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylp-
ropanoic acid
3-{6-[(diphenylacetyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{6-[(2-hydroxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{6-[(4-ethylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-(6-{[3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoyl]amino}-1H-benzimi-
dazol-1-yl)- 3-phenylpropanoic acid
3-{6-[(3-bromo-2,6-dimethoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylp-
ropanoic acid
3-{6-[(4-bromo-2,3,5,6-tetrafluorobenzoyl)amino]-1H-benzimidazol-1-yl}-3-
phenylpropanoic acid
3-{6-[(5-bromo-2-furoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{6-[(3-iodobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{6-[(2-formylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{6-[(2-bromobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{6-[(3-bromobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-(6-{[(5-bromo-3-pyridinyl)carbonyl]amino}-1H-benzimidazol-1-yl)-3-phenyl-
propanoic acid
3-(6-{[(5-bromo-2-thienyl)carbonyl]amino}-1H-benzimidazol-1-yl)-3-phenylpr-
opanoic acid
3-{6-[(2-bromo-5-methoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropa-
noic acid
3-{6-[(4-bromo-2-methylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropan-
oic acid
3-{6-[(4-bromo-2-chlorobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropan-
oic acid
3-(6-{[(2E)-3-(3-bromo-4-fluorophenyl)-2-propenoyl]amino}-1H-benzimidazol--
1-yl)-3- phenylpropanoic acid
3-(6-{[(2E)-3-(6-bromo-1,3-benzodioxol-5-yl)-2-propenoyl]amino}-1H-benzimi-
dazol-1- yl)-3-phenylpropanoic acid
3-{6-[(2-oxo-3-phenylpropanoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropan-
oic acid
3-{6-[(4-oxopentanoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-phenyl-3-[6-({[2-(phenylsulfanyl)-3-pyridinyl]carbonyl}amino)-1H-benzimi-
dazol-1- yl]propanoic acid
3-{6-[(2-hydroxy-5-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropa-
noic acid
3-{6-[(2-hydroxy-3-methoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpro-
panoic acid
3-(6-{[(4-hydroxy-3-methoxyphenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-
phenylpropanoic acid
3-{6-[(2,5-dihydroxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-{6-[(2-hydroxy-3-methylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylprop-
anoic acid
3-{6-[(3-hydroxy-4-methylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylprop-
anoic acid
3-(6-{[(3-hydroxy-4-methoxyphenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-
phenylpropanoic acid
3-(6-{[(4,7-dimethylpyrazolo[5,1-c][1,2,4]triazin-3-yl)carbonyl]amino}-1H--
benzimidazol- 1-yl)-3-phenylpropanoic acid
3-(6-{[3-(2,4-dihydroxyphenyl)propanoyl]amino}-1H-benzimidazol-1-yl)-3-
phenylpropanoic acid
3-(6-{[(3,5-ditert-butyl-4-hydroxyphenyl)acetyl]amino}-1H-benzimidazol-1-y-
l)-3- phenylpropanoic acid
3-(6-{[(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl)carbonyl-
]amino}-1H- benzimidazol-1-yl)-3-phenylpropanoic acid
3-{6-[(5-formyl-2-hydroxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylprop-
anoic acid
3-{6-[(3,5-dichloro-2-hydroxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenyl-
propanoic acid
3-phenyl-3-{6-[(2,4,6-trihydroxybenzoyl)amino]-1H-benzimidazol-1-yl}propan-
oic acid
3-{6-[(2-hydroxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
3-phenyl-3-{6-[(2,3,5-trichloro-6-hydroxybenzoyl)amino]-1H-benzimidazol-1--
yl}propanoic acid
3-{6-[(5-chloro-2-hydroxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylprop-
anoic acid
3-{6-[(5-bromo-2-hydroxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropa-
noic acid, and
3-{6-[(2-hydroxy-4-methylbenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylprop-
anoic acid
3-(6-{[(3,4-dihydroxyphenyl)acetyl]amino}-1H-benzimidazol-1-yl)-3-phenylpr-
opanoic acid; and
3-{6-[(2-fluoro-6-iodobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropano-
ic acid
or a pharmaceutically acceptable salt thereof.
5. A composition comprising a compound according to claim 1, or a
pharmaceutically acceptable salt thereof; and a pharmaceutically
acceptable carrier.
6. A composition comprising a compound according to claim 1, or a
pharmaceutically acceptable salt thereof; and an anti-neoplastic,
anti-tumor, anti-angiogenic, or chemotherapeutic agent.
7. A composition comprising a compound according to claim 1, or a
pharmaceutically acceptable salt thereof; and a cytotoxic cancer
therapeutic agent.
8. A composition comprising a compound according to claim 1, or a
pharmaceutically acceptable salt thereof; and an angiogenesis
inhibiting cancer therapeutic agent.
Description
BACKGROUND OF THE INVENTION
The present invention is directed to novel compounds that are
useful in the treatment of abnormal cell growth, such as cancer, in
mammals. This invention is also directed to a method of using such
compounds in the treatment of abnormal cell growth in mammals,
especially humans, and to pharmaceutical compositions containing
such compounds.
The integrins comprise a family of cell surface receptors are
expressed in many tissues. A major function of this class of
receptors is to promote adhesion events between cells and other
cells, or between cells and proteins of the extracellular matrix
(ECM). On the cell surface, integrins can form complexes with other
receptors, proteases, and integrin-associated proteins (IAPs).
Within the cytoplasm, integrins interact with cytoskeletal
proteins, adaptor proteins, and signaling molecules. The adhesion
events that result in integrin ligation generate intracellular
signals that ultimately regulate diverse cell fates such as
adhesion, survival, migration, invasion and differentiation. Some
integrins have been implicated in human pathology, particularly
diseases associated with undesirable forms of angiogenesis, scar
formation, inflammation and cell growth or survival.
The structure of integrin molecules has been reviewed periodically
over the last decade [eg. Seftor, Am. J. Path., 153, (1998),
1347-1351]. Integrins are heterodimeric glycoproteins composed of
an .alpha. subunit non-covalently associated with a .beta. subunit.
To date, at least 14.alpha. subunits and 8.beta. subunits have been
described, which can associate in various combinations to form the
approximately 20 different integrins currently known. Diversity may
be limited by differences in affinity between subunits; for
example, the human .alpha..sub.v subunit can associate with a
number of .beta. partners to form multiple integrins
(.alpha..sub.v.beta..sub.1, .alpha..sub.v.beta..sub.3,
.alpha..sub.v.beta..sub.5, .alpha..sub.v.beta..sub.6,
.alpha..sub.v.beta..sub.8) whereas the .alpha..sub.IIb subunit is
identified only in .alpha..sub.IIb.beta..sub.3 integrins. An
important feature of integrin biology is that many integrins
recognize short (3 to 6 amino acid) sequences within their
corresponding ligands. In particular, the tripeptide RGD
(Arg-Gly-Asp) was the first defined integrin recognition site,
although others have since been identified by different
experimental approaches [Healy et al., Biochemistry, 34, (1995),
3948-3955]. The RGD site is found in a variety of adhesive
proteins, including vitronectin, fibronectin, fibrinogen, von
Willebrand factor, osteopontin and other adhesive proteins.
Integrin .alpha..sub.v.beta..sub.3 is promiscuous in its ability to
recognize the RGD sequence in different proteins that serve as its
ligands (examples include vitronectin, fibrinogen, denatured
collagen and osteopontin), whereas other integrins recognize RGD
sequences in more restricted contexts. The affinity by which
certain integrins bind ligands can be regulated by intracellular
signals that are transduced to the extracellular ligand-binding
domain. Such "inside-out" signaling serves to modulate integrin
adhesion events in response to environmental cues, such as those
that induce platelet activation or inflammation.
Integrin .alpha..sub.v.beta..sub.3, also known as the classical
vitronectin receptor, is relatively restricted in its expression in
adult tissues, being found on a subset of inflammatory cells,
osteoclasts, smooth muscle cells and fibroblasts. This integrin is
not expressed appreciably in the mature epithelium or endothelium,
but becomes highly expressed on proliferating endothelial cells in
wounds, in inflammatory states such as endometriosis, and in the
vasculature of solid tumors [Clark et al., Am. J. Path., 148,
(1996), 1407-1421; Hii et al., Human Reproduction, 13, (1998),
1030-1035; Brooks et al., Science, 264, (1994), 569-571].
Expression of .alpha..sub.v.beta..sub.3 is considered a marker for
ongoing angiogenesis, and in adults, radiolabeled antibodies to
.alpha..sub.v.beta..sub.3 have been used to detect the vascular
beds of solid tumors [Sipkins et al., Nat. Med., 4, (1998),
623-626].
Functional roles for .alpha..sub.v.beta..sub.3 have been examined
by inhibiting .alpha..sub.v.beta..sub.3/ligand interactions by
pharmacological or genetic manipulation. For example, the
interactions between .alpha..sub.v.beta..sub.3 and its ligands can
be antagonized by peptides spanning the RGD sequence, by
peptidomimetic compounds, and by disintegrins, a class of
integrin-binding proteins derived mainly from snake venoms. Several
antibodies can bind .alpha..sub.v.beta..sub.3 in a manner that
blocks ligand accessibility, and are particularly useful as
selective .alpha..sub.v.beta..sub.3 antagonists. Such studies have
defined a role for .alpha..sub.v.beta..sub.3 during tissue
remodeling events, such as those associated with angiogenesis and
embryonic neovascularization [Brooks et al., Cell, 79, (1994),
1157-1164; Drake et al., J. Cell Sci., 108, (1995), 2655-2661].
Selective disruption of .alpha..sub.v.beta..sub.3 by a neutralizing
monoclonal antibody, LM609, disrupts angiogenesis in the chicken
chorioallantoic membrane (CAM), and in the mouse retina and rabbit
cornea. LM609 also inhibits neovascularization in the quail embryo.
Inhibition of angiogenesis is associated with endothelial cell
apoptosis, and the ability of .alpha..sub.v.beta..sub.3 to promote
cell survival has been confirmed in vitro [Petitclerc et al.,
Cancer Research, 59, (1999), 2724-2730]. Importantly, selective
.alpha..sub.v.beta..sub.3 antagonists do not appear to harm the
mature vasculature, and are tolerated in adult animals [Brooks et
al., J. Clin. Invest., 96, (1995), 1815-1822; reviewed by Elicieri
and Cheresh, J. Clin. Invest., 103, (1999), 1227-1230].
The ability of .alpha..sub.v.beta..sub.3 to transduce survival
signals for vascular endothelial cells suggests that antagonists of
this integrin would be useful agents for inhibiting angiogenesis in
tumors, and ultimately, for inhibiting tumor growth. Antibody LM609
has been shown to block angiogenesis in the chicken chorioallantoic
membrane (CAM) induced by cytokines (bFGF, TNF-.alpha.) and
melanoma implants. LM609 also impeded the growth of four distinct
tumors inoculated onto the CAM [Brooks et al., Science, 264,
(1994), 569-57; Brooks et al., Cell, 79, (1994), 1157-1164]. The
inhibition of the development of human blood vessels and tumor
growth in a SCID mouse/human skin chimeric model has also been
reported [Brooks et al., J. Clin. Invest., 96, (1995),
1815-1822].
Multiple cytokines and secreted factors can induce angiogenesis. In
the rabbit cornea, angiogenesis induced by bFGF or TNF-.alpha. was
inhibited by LM609, but was not inhibited appreciably by a
neutralizing antibody (P1F6) that binds a second vitronectin
receptor, .alpha..sub.v.beta..sub.5 [Friedlander et al., Science,
270, (1995), 1500-1502]. In contrast, P1F6 was more effective than
LM609 when angiogenesis was induced by VEGF. The same tendencies
were noted when angiogenesis was induced in the chick CAM, although
LM609 retained a partial ability to inhibit VEGF-induced
angiogenesis in this system. Neither antibody was as effective as
an RGD peptide that blocked both .alpha..sub.v.beta..sub.3 and
.alpha..sub.v.beta..sub.5. For some tumors, it may thus be
preferable to utilize a drug that blocks both
.alpha..sub.v.beta..sub.3 and .alpha..sub.v.beta..sub.5 in others
it may be more preferable to inhibit .alpha..sub.v.beta..sub.3
selectively whilst some other tumors or ocular disorders (see
below) may respond best to selective inhibitors of
.alpha..sub.v.beta..sub.5.
Integrin .alpha..sub.v.beta..sub.3 can transduce survival signals
in proliferating vascular endothelial cells. Ectopic integrin
expression on a subset of tumors might also promote inappropriate
survival of transformed cells in cancer patients. Human cutaneous
melanoma cells express multiple integrin types, but
.alpha..sub.v.beta..sub.3 is restricted to cells within the
vertical growth phase, as compared to radial growth phase cells
found in nevi [Albelda et al., Cancer Research, 50, (1990),
6757-6764]. Subsequent studies have demonstrated that forced
expression of the .beta..sub.3 subunit alone results in association
with pre-existing .alpha..sub.v subunits, expression of
.alpha..sub.v.beta..sub.3 and a concomitant transition to a more
malignant phenotype [Hsu et al., Am. J. Path., 153, (1998),
1435-1442]. Ultimately, expression of .alpha..sub.v.beta..sub.3 on
tumor cells may transduce survival signals, as well as recruit
matrix metalloproteinases (eg. MMP-2) and other integrin-binding
proteins that facilitate invasion [Brooks et al., Cell, 92, (1998),
391-400]. Specific inhibitors of .alpha..sub.v.beta..sub.3 may be
used to directly inhibit certain tumors, particularly melanomas,
where .alpha..sub.v.beta..sub.3 expression has been particularly
well documented.
Antagonists of .alpha..sub.v integrins inhibit vascular endothelial
cell survival, implying that such antagonists might also be used
for the treatment of indications such as ocular disorders
associated with angiogenesis [age-related macular degeneration
(ARMD), presumed ocular histoplasmosis syndrome (POHS), and retinal
neovascularization from proliferative diabetic retinopathy (PDR)].
Friedlander et al., [Proc. Natl. Acad. Sci. USA, 93, (1996),
9764-9769] reported that .alpha..sub.v.beta..sub.3 was selectively
found on blood vessels from patients with ARMD and POHS, whereas
.alpha..sub.v.beta..sub.3 and .alpha..sub.v.beta..sub.5 were
co-expressed on blood vessels from patients with PDR. Normal ocular
vessels were largely negative for both integrins, suggesting that
chemical inhibition of .alpha..sub.v.beta..sub.3 and/or
.alpha..sub.v.beta..sub.5 may be useful for the treatment of these
blinding disorders.
Rheumatoid arthritis (RA) is an inflammatory disease that
ultimately causes joint destruction. The RA joint is characterized
by excessive cell proliferation and vascularization, and synovial
blood vessels from patients with this disease show increased levels
of .alpha..sub.v.beta..sub.3 [Johnson et al., Arthritis Rheum., 36,
(1993), 137-146]. In a rabbit model of antigen-induced arthritis
(AIA) augmented by bFGF, injection of a cyclic peptide with
selectivity for .alpha..sub.v.beta..sub.3 reduced angiogenesis,
pannus formation and cartilage erosion (Strogard et al., J. Clin.
Invest., 103, (1999), 47-54]. The peptide inhibitor, c[RGDfV], was
approximately 100-fold more potent for .alpha..sub.v.beta..sub.3
inhibition relative to .alpha..sub.v.beta..sub.5 inhibition in
vitro (IC.sub.50: 4.8 vs 450 nM, respectively). A second peptide,
c[RGDf(N-Me)V], exhibited a similar in vitro potency towards
.alpha..sub.v.beta..sub.3 and improved potency to
.alpha..sub.v.beta..sub.5 (2.3 vs 37 nM, respectively), but was a
slightly inferior antagonist of RA. Inhibitors of
.alpha..sub.v.beta..sub.3 may therefore have utility in the
treatment of patients with RA.
Integrin .alpha..sub.v.beta..sub.3 contributes to the process of
bone resorption, by facilitating the adhesion of osteoclasts to
ligands such as bone sialoprotein and osteopontin [Ross et al., J.
Biol. Chem., 268, (1993), 9901-9907]. When bone resorption by
osteoclasts exceeds bone-forming activity, osteoporosis (loss of
bone) results. Osteoporosis is a major health problem that is
associated with an increased risk of bone fractures,
incapacitation, pain and mortality. Neutralizing antibodies to
.alpha..sub.v.beta..sub.3 as well as RGD peptides, and
peptidomimetic compounds have been shown to inhibit the resorption
of bone and dentine by osteoclasts (Engleman et al., J. Clin.
Invest., 99, (1997), 2284-2292; Horton et al., Exp. Cell Res., 195,
(1991), 368-375; Sato et al., J. Cell Biol., 111, (1990),
1713-1723; Fisher et al., Endocrinology, 132, (1993), 1411-1413].
Antagonism of osteoclasts by .alpha..sub.v.beta..sub.3 selective
antagonists appears to be a promising approach towards restoring an
equilibrium to bone remodeling in osteoporosis.
Other diseases characterized by excessive bone loss include Paget's
disease, humoral hypercalcemia of malignancy (HHM), hypercalcemia
from tumors metastatic to bone, and osteoporosis induced by
glucocorticoid treatment. Caron et al. [Cancer Research, 58,
(1998), 1930-1935] have recently reported that a peptidomimetic
antagonist of .alpha..sub.v.beta..sub.3, SC-68448, could inhibit
tumor growth and the resulting HHM in a SCID mouse/rat Leydig cell
tumor model. Patients with any of the above disorders might benefit
from treatment with selective inhibitors of
.alpha..sub.v.beta..sub.3.
Integrin .alpha..sub.v.beta..sub.3 is expressed on vascular smooth
muscle cells (VSMC), and antagonists of this integrin have
therefore been evaluated for inhibition of coronary restenosis. RGD
containing peptides inhibit neointimal hyperplasia in various small
animal models, such as rat, rabbit, hamster and guinea pig [Choi et
al., J. Vasc. Surgery, 19, (1994), 125-134]. Another
.alpha..sub.v.beta..sub.3 antagonist, XJ 735, was shown to be
selective for .alpha..sub.v.beta..sub.3 relative to other integrins
(.alpha..sub.v.beta..sub.5, .alpha..sub.IIb.beta..sub.3,
.alpha..sub.4.beta..sub.1, .alpha..sub.5.beta..sub.1), and to
inhibit coronary restenosis in a porcine coronary injury model
[Srivasta et al., Cardiovascular Research, 36, (1997), 408-428].
This study confirms the idea that selective
.alpha..sub.v.beta..sub.3 antagonism can impede neointimal cell
proliferation and stenosis following vessel injury. The study also
supports the possibility that the positive long-term effects of
Abciximab (ReoPro, chimeric 7E3 Fab) in the EPIC trial may have
been partly due to the inhibition of .alpha..sub.v.beta..sub.3.
A number of microbial pathogens, including adenovirus,
hantaviruses, Borrelia burgdorferi, Yersinia spp., Bordetella
pertussis, and group A Streptococcus, bind integrins, usually
through an RGD motif on a cell surface protein. Some of these
proteins serve as virulence factors [Stockbauer et al., Proc. Natl.
Acad. Sci. USA, 96, (1999), 242-247]. Integrin antagonists may
therefore be useful in inhibiting certain forms of microbial
infections.
DD 123466 shows processes for making substituted
benzimidazoles.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the Formula 1
##STR00002##
or a pharmaceutically acceptable salt or solvate thereof,
wherein:
the dashed line designates that a double bond or a single bond
connects the nitrogen at the three position with the carbon at the
two position;
each A and A' is independently a direct bond, --C(O)N(R.sup.4)--,
--N(R.sup.4)C(O)--, --N(R.sup.4)SO.sub.2--, --SO.sub.2N(R.sup.4)--,
--N(R.sup.4)C(O)(CR.sup.4R.sup.5).sub.pNHC(O)--,
--N(R.sup.4)C(O)(CR.sup.4R.sup.5).sub.pN(R.sup.4)--,
--N(R.sup.4)C(S)(CR.sup.4R.sup.5).sub.pN(R.sup.4)--,
--N(R.sup.4)C(O)(CR.sup.4R.sup.5).sub.pC(O)--, --N(R.sup.4)C(O)O--,
--N(R.sup.4)C(O)S--, --C(O)--, --N(R.sup.3)--, --S-- or --O--,
wherein p is an integer from 0 to 5 and the left dash of the
foregoing groups is attached to the benzimidazole ring of the
compound of Formula 1;
X.sup.1 is
--(CR.sup.4R.sup.5).sub.m--C(A'-R.sup.1a)(A-R.sup.1)--(CR.sup.4R.sup.5).s-
ub.nCO.sub.2H or
--(CR.sup.4R.sup.5).sub.m--C(A-R.sup.1).dbd.C(R.sup.4)--(CR.sup.4R.sup.5)-
.sub.n--CO.sub.2H, wherein m and n are each independently an
integer from 0 to 4 and the (CR.sup.4R.sup.5).sub.m and
(CR.sup.4R.sup.5), moieties of the foregoing X.sup.1 groups
optionally include one or two carbon-carbon double or triple
bonds;
X.sup.2 is H, C.sub.1-C.sub.20 alkyl, C.sub.2-C.sub.20 alkenyl,
C.sub.2-C.sub.20 alkynyl,
--(CR.sup.4R.sup.5).sub.r(C.sub.3-C.sub.20 cycloalkyl),
--(CR.sup.4R.sup.5).sub.t(C.sub.6-C.sub.10 aryl), or
--(CR.sup.4R.sup.5).sub.t(4 to 12 membered heterocyclic),
wherein
each X.sup.2 group, except H, is substituted by X.sup.3,
each t is independently an integer from 0 to 5,
said alkyl, alkenyl and alkynyl groups optionally contain 1 or 2
hetero moieties selected from O, --S(O).sub.j-- wherein j is an
integer from 0 to 2, and --N(R.sup.4)-- with the proviso that two O
atoms, two S atoms, or an O and S atom are not attached directly to
each other, and the proviso that an O atom, a S atom or a N atom
are not attached directly to a triple bond or non-aromatic double
bond;
said cycloalkyl, aryl and heterocyclic X.sup.2 groups are
optionally fused to one or two ring systems independently selected
from a benzene ring, a C.sub.5-C.sub.8 cycloalkyl group, and a 4 to
10 membered heterocyclic group;
--(CR.sup.4R.sup.5).sub.t-- optionally includes a carbon-carbon
double or triple bond where t is an integer from 2 to 5,
or where t is 1 the --(CR.sup.4R.sup.5).sub.t-- moiety of
--(CR.sup.4R.sup.5).sub.t(4 to 12 membered heterocyclic and
--(CR.sup.4R.sup.5).sub.t(C.sub.3-C.sub.20 cycloalkyl) optionally
is attached by a carbon-carbon double bond to a carbon of the
cycloalkyl group or a non-aromatic carbon of the 4 to 12 membered
heterocyclic group;
said cycloalkyl optionally includes one or two carbon-carbon double
or triple bonds;
and X.sup.2, except when H, optionally is substituted by 1 to 5
R.sup.2 groups;
X.sup.3 is H or a functional group which forms biological
interactions similar to those of the guanadinyl group
(--NH(.dbd.NH)NH.sub.2) present in the amino acid arginine such as
2-aminoimidazoyl, 2-aminobenzimidazoyl, 2-aminopyridyl,
2-aminopyrimidyl, 2-aminopyrazinyl and others disclosed in Keenan
et al, Bioorg. Med. Chem. Lett., 9(1999), 1801, incorporated herein
by reference, wherein each of the foregoing X.sup.3 groups, other
than H, is optionally substituted by 1 or 2 R.sup.2 groups;
X.sup.4 is H, C.sub.1-C.sub.10 alkyl, --NR.sup.3R.sup.4,
--SR.sup.3, or --OR.sup.3;
each X.sup.5 and R.sup.2 is independently selected from
C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10
alkynyl, oxo (.dbd.O), thioxo (.dbd.S), halo, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,
--OR.sup.3, --C(O)R.sup.3, --C(O)OR.sup.3, --NR.sup.4C(O)OR.sup.6,
--NR.sup.4C(O)R.sup.3, --OC(O)R.sup.3, --NR.sup.4SO.sub.2R.sup.6,
--SO.sub.2NR.sup.3R.sup.4, --NR.sup.4C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --O--N.dbd.CR.sup.3R.sup.4,
--NR.sup.4C(O)NR.sup.3R.sup.4, --NR.sup.4C(S)NR.sup.3R.sup.4,
--NR.sup.3R.sup.4,
--S(O).sub.j(CR.sup.4R.sup.5).sub.t(C.sub.6-C.sub.10 aryl),
--S(O).sub.j(CR.sup.4R.sup.5).sub.t(4 to 12 membered heterocyclic),
--S(O).sub.j(C.sub.1-C.sub.6 alkyl),
--(CR.sup.4R.sup.5).sub.t(C.sub.6-C.sub.10 aryl),
--(CR.sup.4R.sup.5).sub.pC(O)(CR.sup.4R.sup.5).sub.t(C.sub.6-C.sub.10
aryl),
--(R.sup.4R.sup.5).sub.pO(CR.sup.4R.sup.5).sub.t(C.sub.6-C.sub.10
aryl), --NR.sup.4(CR.sup.4R.sup.5).sub.t(C.sub.6-C.sub.10 aryl),
--(CR.sup.4R.sup.5).sub.t(4 to 12 membered heterocyclic), and
--(CR.sup.4R.sup.5).sub.pC(O)(CR.sup.4R.sup.5).sub.t(4 to 12
membered heterocyclic), wherein each t is independently an integer
from 0 to 5, each p is independently an integer from 0 to 5, and
each j is an integer from 0 to 2; said alkyl, alkenyl and alkynyl
groups optionally contain 1 or 2 hetero moieties selected from O,
--S(O).sub.j-- wherein j is an integer from 0 to 2, and
--N(R.sup.3)-- with the proviso that two O atoms, two S atoms, or
an O and S atom are not attached directly to each other, and the
proviso that an O atom, a S atom or a N atom are not attached
directly to a triple bond or a non-aromatic double bond; said
cycloalkyl, aryl and heterocyclic R.sup.2 groups are optionally
fused to a C.sub.6-C.sub.10 aryl group, a C.sub.5-C.sub.8
cycloalkyl group, or a 4 to 12 membered heterocyclic group; and
said alkyl, alkenyl, alkynyl, aryl and heterocyclic moieties of the
foregoing R.sup.2 groups are optionally substituted by 1 to 5
substituents independently selected from oxo (.dbd.O), thioxo
(.dbd.S), halo, cyano, nitro, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, azido, --NR.sup.4SO.sub.2R.sup.6,
--SO.sub.2NR.sup.3R.sup.4, --C(O)R.sup.3, --C(O)OR.sup.3,
--OC(O)R.sup.3, --NR.sup.4C(O)OR.sup.6, --NR.sup.4C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --NR.sup.3R.sup.4, --OR.sup.3,
C.sub.1-C.sub.10 alkyl, --S(O).sub.j(C.sub.1-C.sub.6 alkyl),
--(CR.sup.4R.sup.5).sub.t(C.sub.6-C.sub.10 aryl), and
--(CR.sup.4R.sup.5).sub.t(4 to 12 membered heterocyclic), wherein
each t is independently an integer from 0 to 5 and each j is
independently an integer from 0 to 2;
each R.sup.1 and R.sup.1a is independently selected from H,
C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10
alkynyl, --(CR.sup.4R.sup.5).sub.t(C.sub.6-C.sub.10 aryl) and
--(CR.sup.4R.sup.5).sub.t(4 to 12 membered heterocyclic); wherein t
is an integer from 0 to 5; and R.sup.1, except when H, is
optionally substituted with 1 to 5 R.sup.2 groups;
each R.sup.3 is independently selected from H, C.sub.1-C.sub.10
alkyl, --(CR.sup.4R.sup.5).sub.t(C.sub.6-C.sub.10 aryl), and
--(CR.sup.4R.sup.5).sub.t(4 to 12 membered heterocyclic), wherein
each t is independently an integer from 0 to 5; said alkyl group
optionally includes 1 or 2 hetero moieties selected from O,
--S(O).sub.j-- wherein j is an integer ranging from 0 to 2, and
--N(R.sup.4)-- with the proviso that two 0 atoms, two S atoms, or
an O and S atom are not attached directly to each other; said
cycloalkyl, aryl and heterocyclic R.sup.3 groups are optionally
fused to a C.sub.6-C.sub.10 aryl group, a C.sub.5-C.sub.8
cycloalkyl group, or a 4 to 12 membered heterocyclic group; and
R.sup.3, except when H, is optionally substituted by 1 to 5
substituents independently selected from oxo, halo, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,
--C(O)R.sup.4, --C(O)OR.sup.4, --OC(O)R.sup.4,
--NR.sup.4C(O)R.sup.5, --C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5,
hydroxy, C.sub.1-C.sub.6 alkyl, trifluoromethyl, trifluoromethoxy,
and C.sub.1-C.sub.6 alkoxy, and with the proviso that R.sup.3 must
be attached through a carbon atom unless R.sup.3 is H;
each R.sup.4 and R.sup.5 is independently H or C.sub.1-C.sub.6
alkyl; or where R.sup.4 and R.sup.5 are attached to the same carbon
atom, R.sup.4 and R.sup.5 may be taken together to form a
C.sub.3-C.sub.10 cycloalkyl group;
each R.sup.6 is independently selected from C.sub.1-C.sub.10 alkyl,
--(CR.sup.4R.sup.5).sub.t(C.sub.6-C.sub.10 aryl), and
--(CR.sup.4R.sup.5).sub.t(4 to 12 membered heterocyclic), wherein
each t is independently an integer from 0 to 5; said alkyl group
optionally includes 1 or 2 hetero moieties selected from O,
--S(O).sub.j-- wherein j is an integer ranging from 0 to 2, and
--N(R.sup.4)-- with the proviso that two O atoms, two S atoms, or
an O and S atom are not attached directly to each other; said
cycloalkyl, aryl and heterocyclic R.sup.6 groups are optionally
fused to a C.sub.6-C.sub.10 aryl group, a C.sub.5-C.sub.8
cycloalkyl group, or a 4 to 12 membered heterocyclic group; and
R.sup.6 is optionally substituted by 1 to 5 substituents
independently selected from oxo, halo, cyano, nitro,
trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,
--C(O)R.sup.4, --C(O)OR.sup.4, --OC(O)R.sup.4,
--NR.sup.4C(O)R.sup.5, --C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5,
hydroxy, C.sub.1-C.sub.6 alkyl, trifluoromethyl, trifluoromethoxy,
and C.sub.1-C.sub.6 alkoxy.
In a specific embodiment of the present invention, the A moiety in
-A-X.sup.2 is selected from a direct bond, --C(O)NH--, --NHC(O)--,
--SO.sub.2NH--, --NHSO.sub.2--, --NHC(O)NH--, and --NHC(S)NH--.
In another specific embodiment of the present invention, X.sup.1 is
selected from --CH.sub.2--CH(AR.sup.1)--CO.sub.2H,
--CH(AR.sup.1)--CH.sub.2--CO.sub.2H, --CH(AR.sup.1)--CO.sub.2H,
--C(AR.sup.1)(A'R.sup.1a)--CH.sub.2--CO.sub.2H,
--CH.sub.2--C(AR.sup.1)(A'R.sup.1a)--CO.sub.2H,
--C(AR.sup.1)(A'R.sup.1a)--CO.sub.2H and
--C(AR.sup.1).dbd.CHCO.sub.2H.
In another specific embodiment of the present invention, -A-X.sup.2
and X.sup.5 are both H, the dashed line in Formula 1 between the
nitrogen at the three position and carbon at the two position
designates a double bond, X.sup.4 is H, and X.sup.1 is
--C(AR.sup.1)(A'R.sup.1a)--CH.sub.2--CO.sub.2H. More specifically,
such compounds include those wherein X.sup.1 is
--CH(AR.sup.1)--CH.sub.2--CO.sub.2H. More specifically, such
compounds also include those wherein X.sup.1 is
--CH(AR.sup.1)--CH.sub.2--CO.sub.2H, A is a direct bond or
--CH.sub.2--, and R.sup.1 is phenyl optionally substituted by 1 or
2 R.sup.2 groups.
In another specific embodiment of the present invention, -A-X.sup.2
is --NHC(O)X.sup.2, X.sup.5 is H, the dashed line in Formula 1
between the nitrogen at the three position and carbon at the two
position designates a double bond, X.sup.4 is H, and X.sup.1 is
--CH(AR.sup.1)--CH.sub.2--CO.sub.2H in which A is a direct bond or
--CH.sub.2--, and R.sup.1 is phenyl optionally substituted by 1 or
2 R.sup.2 groups. More specifically, X.sup.2 is phenyl optionally
substituted by 1 to 4 R.sup.2 groups. More specifically, X.sup.2 is
pyridyl optionally substituted by 1 to 3 R.sup.2 groups.
In another specific embodiment of the present invention, the dashed
line in Formula 1 between the nitrogen at the three position and
carbon at the two position designates a double bond, X.sup.4 is H,
and X.sup.1 is --CH(AR.sup.1)--CH.sub.2--CO.sub.2H in which A is a
direct bond or --CH.sub.2--, and R.sup.1 is pyridyl, naphthyl, or
phenyl optionally substituted by 1 or 2 R.sup.2 groups, and X.sup.5
is selected from nitro, --NR.sup.3R.sup.4, and
--NR.sup.4SO.sub.2R.sup.6. More specifically X.sup.5 is selected
from nitro, amino and phenylsulfonylamino.
In another specific embodiment of the present invention, X.sup.3 is
selected from H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.12
cycloalkyl, 5 to 12 membered heterocyclic, and guanidine group
mimetics, and said groups, other than H, are optionally substituted
by R.sup.2;
Preferred compounds include those selected from the group
consisting of: 3-(1H-Benzimidazol-1-yl)-3-(4-ethylphenyl)propanoic
acid;
3-Phenyl-3-[6-(trifluoromethyl)-1H-benzimidazol-1-yl]propanoic
acid; (3R)-3-(1H-Benzimidazol-1-yl)-3-phenylpropanoic acid;
(3S)-3-(1H-Benzimidazol-1-yl)-4-phenylbutanoic acid;
3-(1H-Benzimidazol-1-yl)-3-(4-chlorophenyl)propanoic acid;
3-Phenyl-3-(4-{4-[(1,4,5,6-tetrahydro-2-pyrimidinylamino)carbonyl]-1-pipe-
ridinyl}-1H-benzimidazol-1-yl)propanoic acid;
3-{5-[(3-Nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid;
3-{5-[(3-Aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoi-
c acid;
3-{5-[(3-{[Amino(imino)methyl]amino}benzoyl)amino]-1H-benzimidazol-
-1-yl}-3-phenylpropanoic acid;
3-{5-[(4-{[Amino(imino)methyl]amino}benzoyl)amino]-1H-benzimidazol-1-yl}--
3-phenylpropanoic acid;
3-{5-[(Anilinocarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid;
3-{5-[(2-Phenoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropan-
oic acid;
3-{5-[(2,6-Dimethoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-pheny-
lpropanoic acid;
3-Phenyl-3-[5-({[2-(phenylsulfanyl)-3-pyridinyl]carbonyl}amino)-1H-benzim-
idazol-1-yl]propanoic acid;
3-(5-{[(2-Phenoxy-3-pyridinyl)carbonyl]amino}-1H-benzimidazol-1-yl)-3-phe-
nylpropanoic acid;
3-{5-[(2-Hydroxy-5-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylprop-
anoic acid;
3-{6-[(2-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid;
3-(6-{[3-(1H-Indol-3-yl)propanoyl]amino}-1H-benzimidazol-1-yl)-3-ph-
enylpropanoic acid;
3-Phenyl-3-[6-({[2-(phenylsulfanyl)-3-pyridinyl]carbonyl}amino)-1H-benzim-
idazol-1-yl]propanoic acid;
3-{6-[(2-Bromo-5-methoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylprop-
anoic acid;
3-Phenyl-3-(6-{[(4-phenyl-1,2,3-thiadiazol-5-yl)carbonyl]amino}-1H-benzim-
idazol-1-yl)propanoic acid;
3-{6-[(3-Bromo-2,6-dimethoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenyl-
propanoic acid
3-Phenyl-3-{6-[(2,3,5-trichloro-6-hydroxybenzoyl)amino]-1H-benzimidazol-1-
-yl}propanoic acid;
3-(5-Nitro-1H-benzimidazol-1-yl)-3-(3-pyridinyl)propanoic acid;
3-(5-Amino-1H-benzimidazol-1-yl)-3-(3-pyridinyl)propanoic acid;
3-{5-[(Phenylsulfonyl)amino]-1H-benzimidazol-1-yl}-3-(3-pyridinyl)propano-
ic acid; 3-(2-Naphthyl)-3-(5-nitro-1H-benzimidazol-1-yl)propanoic
acid; 3-(5-Amino-1H-benzimidazol-1-yl)-3-(2-naphthyl)propanoic
acid;
3-(2-Naphthyl)-3-{5-[(phenylsulfonyl)amino]-1H-benzimidazol-1-yl}propanoi-
c acid
3-(5-Amino-1H-benzimidazol-1-yl)-3-(4-methoxyphenyl)propanoic acid;
3-(4-Methoxyphenyl)-3-{5-[(phenylsulfonyl)amino]-1H-benzimidazol-1-yl}pro-
panoic acid;
1-(2-Carboxy-1-phenylethyl)-1H-benzimidazole-5-carboxylic acid;
3-[5-(Anilinocarbonyl)-1H-benzimidazol-1-yl]-3-phenylpropanoic
acid;
3-Phenyl-3-(5-{[4-(2-pyrazinyl)-1-piperazinyl]carbonyl}-1H-benzimid-
azol-1-yl) propanoic acid;
and the pharmaceutically acceptable salts or solvates of the
foregoing compounds.
This invention also relates to a method for the treatment of
abnormal cell growth in a mammal, including a human, comprising
administering to said mammal an amount of a compound of the Formula
1, as defined above, or a pharmaceutically acceptable salt or
solvate thereof, that is effective in treating abnormal cell
growth. In one embodiment of this method, the abnormal cell growth
is cancer, including, but not limited to, lung cancer, bone cancer,
pancreatic cancer, skin cancer, cancer of the head or neck,
cutaneous or intraocular melanoma, uterine cancer, ovarian cancer,
rectal cancer, cancer of the anal region, stomach cancer, colon
cancer, breast cancer, uterine cancer, carcinoma of the fallopian
tubes, carcinoma of the endometrium, carcinoma of the cervix,
carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease,
cancer of the esophagus, cancer of the small intestine, cancer of
the endocrine system, cancer of the thyroid gland, cancer of the
parathyroid gland, cancer of the adrenal gland, sarcoma of soft
tissue, cancer of the urethra, cancer of the penis, prostate
cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of
the bladder, cancer of the kidney or ureter, renal cell carcinoma,
carcinoma of the renal pelvis, neoplasms of the central nervous
system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem
glioma, pituitary adenoma, or a combination of one or more of the
foregoing cancers. In another embodiment of said method, said
abnormal cell growth is a benign proliferative disease, including,
but not limited to, psoriasis, benign prostatic hypertrophy or
restinosis.
This invention also relates to a method for the treatment of
abnormal cell growth in a mammal which comprises administering to
said mammal an amount of a compound of Formula 1, or a
pharmaceutically acceptable salt or solvate thereof, that is
effective in treating abnormal cell growth in combination with an
anti-tumor agent selected from the group consisting of mitotic
inhibitors, alkylating agents, anti-metabolites, intercalating
antibiotics, growth factor inhibitors, cell cycle inhibitors,
enzymes, topoisomerase inhibitors, biological response modifiers,
antibodies, cytotoxics, anti-hormones, and anti-androgens.
The invention also encompasses a pharmaceutical composition that is
comprised of a compound of Formula 1 in combination with a
pharmaceutically acceptable carrier.
Preferably the composition is comprised of a pharmaceutically
acceptable carrier and a non-toxic therapeutically effective amount
of a compound of Formula 1 as described above (or a
pharmaceutically acceptable salt thereof).
This invention also relates to a pharmaceutical composition for the
treatment of abnormal cell growth in a mammal, including a human,
comprising a non-toxic therapeutically effective amount of a
compound of the Formula 1, as described above, or a
pharmaceutically acceptable salt or solvate thereof, that is
effective in treating abnormal cell growth, and a pharmaceutically
acceptable carrier. In one embodiment of said composition, said
abnormal cell growth is cancer, including, but not limited to, lung
cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the
head or neck, cutaneous or intraocular melanoma, uterine cancer,
ovarian cancer, rectal cancer, cancer of the anal region, stomach
cancer, colon cancer, breast cancer, uterine cancer, carcinoma of
the fallopian tubes, carcinoma of the endometrium, carcinoma of the
cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's
Disease, cancer of the esophagus, cancer of the small intestine,
cancer of the endocrine system, cancer of the thyroid gland, cancer
of the parathyroid gland, cancer of the adrenal gland, sarcoma of
soft tissue, cancer of the urethra, cancer of the penis, prostate
cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of
the bladder, cancer of the kidney or ureter, renal cell carcinoma,
carcinoma of the renal pelvis, neoplasms of the central nervous
system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem
glioma, pituitary adenoma, or a combination of one or more of the
foregoing cancers. In another embodiment of said pharmaceutical
composition, said abnormal cell growth is a benign proliferative
disease, including, but not limited to, psoriasis, benign prostatic
hypertrophy or restinosis.
The invention also relates to a pharmaceutical composition for the
treatment of abnormal cell growth in a mammal, including a human,
which comprises an amount of a compound of Formula 1, as defined
above, or a pharmaceutically acceptable salt or solvate thereof,
that is effective in treating abnormal cell growth in combination
with a pharmaceutically acceptable carrier and an anti-tumor agent
selected from the group consisting of mitotic inhibitors,
alkylating agents, anti-metabolites, intercalating antibiotics,
growth factor inhibitors, cell cycle inhibitors, enzymes,
topoisomerase inhibitors, biological response modifiers,
anti-hormones, and anti-androgens.
This invention also relates to a method for the treatment of a
disorder associated with angiogenesis in a mammal, including a
human, comprising administering to said mammal an amount of a
compound of the Formula 1, as defined above, or a pharmaceutically
acceptable salt or solvate thereof, that is effective in treating
said disorder. Such disorders include cancerous tumors such as
melanoma; ocular disorders such as age-related macular
degeneration, presumed ocular histoplasmosis syndrome, and retinal
neovascularization from proliferative diabetic retinopathy;
rheumatoid arthritis; bone loss disorders such as osteoporosis,
Paget's disease, humoral hypercalcemia of malignancy, hypercalcemia
from tumors metastatic to bone, and osteoporosis induced by
glucocorticoid treatment; coronary restenosis; and certain
microbial infections including those associated with microbial
pathogens selected from adenovirus, hantaviruses, Borrelia
burgdorferi, Yersinia spp., Bordetella pertussis, and group A
Streptococcus.
This invention also relates to a method of (and to a pharmaceutical
composition for) treating abnormal cell growth in a mammal which
comprise an amount of a compound of Formula 1, or a
pharmaceutically acceptable salt or solvate thereof, and an amount
of one or more substances selected from anti-angiogenesis agents,
signal transduction inhibitors, and antiproliferative agents, which
amounts are together effective in treating said abnormal cell
growth.
This invention includes a composition comprising a compound
according to Formula 1, or a pharmaceutically acceptable salt or
N-oxide thereof; and a pharmaceutically acceptable carrier.
This invention includes a composition comprising a compound
according to Formula 1, or a pharmaceutically acceptable salt or
N-oxide thereof; and an anti-neoplastic, anti-tumor,
anti-angiogenic, or chemotherapeutic agent.
This invention includes a composition comprising a compound
according to Formula 1, or a pharmaceutically acceptable salt or
N-oxide thereof; and a cytotoxic cancer therapeutic agent.
This invention includes a composition comprising a compound
according to Formula 1, or a pharmaceutically acceptable salt or
N-oxide thereof; and an angiogenesis inhibiting cancer therapeutic
agent.
This invention includes a method of treatment of hyperproliferative
disorder comprising a step of administering an effective amount of
the compound according to Formula 1.
This invention includes a method treatment of hyperproliferative
disorder comprising a step of administering an effective amount of
the compound according to Formula 1, further comprising the step of
administering an anti-neoplastic, anti-tumor, anti-angiogenic, or
chemotherapeutic agent.
Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase
2) inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and
COX-II (cyclooxygenase II) inhibitors, can be used in conjunction
with a compound of Formula 1 in the methods and pharmaceutical
compositions described herein. Examples of useful COX-II inhibitors
include CELEBREX.TM. (alecoxib), valdecoxib, and rofecoxib.
Examples of useful matrix metalloproteinase inhibitors are
described in WO 96/33172 (published Oct. 24, 1996), WO 96/27583
(published Mar. 7, 1996), European Patent Application No.
97304971.1 (filed Jul. 8, 1997), European Patent Application No.
99308617.2 (filed Oct. 29, 1999), WO 98/07697 (published Feb. 26,
1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918
(published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998),
WO 98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul.
16, 1998), European Patent Publication 606,046 (published Jul. 13,
1994), European Patent Publication 931,788 (published Jul. 28,
1999), WO 90/05719 (published May 331, 1990), WO 99/52910
(published Oct. 21, 1999), WO 99/52889 (published Oct. 21, 1999),
WO 99/29667 (published Jun. 17, 1999), PCT International
Application No. PCT/IB98/01113 (filed Jul. 21, 1998), European
Patent Application No. 99302232.1 (filed Mar. 25, 1999), Great
Britain patent application number 9912961.1 (filed Jun. 3, 1999),
U.S. Provisional Application No. 60/148,464 (filed Aug. 12, 1999),
U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No.
5,861,510 (issued Jan. 19, 1999), and European Patent Publication
780,386 (published Jun. 25, 1997), all of which are herein
incorporated by reference in their entirety. Preferred MMP-2 and
MMP-9 inhibitors are those that have little or no activity
inhibiting MMP-1. More preferred, are those that selectively
inhibit MMP-2 and/or MMP-9 relative to the other
matrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6,
MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).
Some specific examples of MMP inhibitors useful in combination with
the compounds of the present invention are AG-3340, RO 32-3555, RS
13-0830, and the compounds recited in the following list:
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl-
)-amino]-propionic acid;
3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]o-
ctane-3-carboxylic acid hydroxyamide; (2R,3R)
1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-pi-
peridine-2-carboxylic acid hydroxyamide;
4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxyl-
ic acid hydroxyamide;
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-
-amino]-propionic acid;
4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxyl-
ic acid hydroxyamide;
3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxyl-
ic acid hydroxyamide; (2R,3R)
1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-pi-
peridine-2-carboxylic acid hydroxyamide;
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-et-
hyl)-amino]-propionic acid;
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro--
pyran-4-yl)-amino]-propionic acid;
3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]o-
ctane-3-carboxylic acid hydroxyamide;
3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]-
octane-3-carboxylic acid hydroxyamide; and
3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxyl-
ic acid hydroxyamide;
and pharmaceutically acceptable salts or solvates of said
compounds.
The compounds of Formula 1, and the pharmaceutically acceptable
salts or solvates thereof, can also be used in combination with
signal transduction inhibitors, such as agents that can inhibit
EGFR (epidermal growth factor receptor) responses, such as EGFR
antibodies, EGF antibodies, and molecules that are EGFR inhibitors;
VEGF (vascular endothelial growth factor) inhibitors; and erbB2
receptor inhibitors, such as organic molecules or antibodies that
bind to the erbB2 receptor, for example, HERCEPTIN.TM. (Genentech,
Inc. of South San Francisco, Calif., USA).
EGFR inhibitors are described in, for example in WO 95/19970
(published Jul. 27, 1995), WO 98/14451 (published Apr. 9, 1998), WO
98/02434 (published Jan. 22, 1998), and U.S. Pat. No. 5,747,498
(issued May 5, 1998). EGFR-inhibiting agents include, but are not
limited to, the monoclonal antibodies C225 and anti-EGFR 22 Mab
(ImClone Systems Incorporated of New York, N.Y., USA), the
compounds ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim),
MDX-447 (Medarex Inc. of Annandale, N.J., USA), and OLX-103 (Merck
& Co. of Whitehouse Station, N.J., USA), VRCTC-310 (Ventech
Research) and EGF fusion toxin (Seragen Inc. of Hopkinton,
Mass.).
VEGF inhibitors, for example SU-5416 and SU-6668 (Sugen Inc. of
South San Francisco, Calif., USA), can also be combined with a
compound of Formula 1. VEGF inhibitors are described in, for
example in WO 99/24440 (published May 20, 1999), PCT International
Application PCT/IB99/00797 (filed May 3, 1999), in WO 95/21613
(published Aug. 17, 1995), WO 99/61422 (published Dec. 2, 1999),
U.S. Pat. No. 5,834,504 (issued Nov. 10, 1998), WO 98/50356
(published Nov. 12, 1998), U.S. Pat. No. 5,883,113 (issued Mar. 16,
1999), U.S. Pat. No. 5,886,020 (issued Mar. 23, 1999), U.S. Pat.
No. 5,792,783 (issued Aug. 11, 1998), WO 99/10349 (published Mar.
4, 1999), WO 97/32856 (published Sep. 12, 1997), WO 97/22596
(published Jun. 26, 1997), WO 98/54093 (published Dec. 3, 1998), WO
98/02438 (published Jan. 22, 1998), WO 99/16755 (published Apr. 8,
1999), and WO 98/02437 (published Jan. 22, 1998), all of which are
herein incorporated by reference in their entirety. Other examples
of some specific VEGF inhibitors are IM862 (Cytran Inc. of
Kirkland, Wash., USA); anti-VEGF monoclonal antibody of Genentech,
Inc. of South San Francisco, Calif.; and angiozyme, a synthetic
ribozyme from Ribozyme (Boulder, Colo.) and Chiron (Emeryville,
Calif.).
ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome p1c),
and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc.
of The Woodlands, Tex., USA) and 2B-1 (Chiron), may be administered
in combination with a compound of Formula 1. Such erbB2 inhibitors
include those described in WO 98/02434 (published Jan. 22, 1998),
WO 99/35146 (published Jul. 15, 1999), WO 99/35132 (published Jul.
15, 1999), WO 98/02437 (published Jan. 22, 1998), WO 97/13760
(published Apr. 17, 1997), WO 95/19970 (published Jul. 27, 1995),
U.S. Pat. No. 5,587,458 (issued Dec. 24, 1996), and U.S. Pat. No.
5,877,305 (issued Mar. 2, 1999), each of which is herein
incorporated by reference in its entirety. ErbB2 receptor
inhibitors useful in the present invention are also described in
U.S. Provisional Application No. 60/117,341, filed Jan. 27, 1999,
and in U.S. Provisional Application No. 60/117,346, filed Jan. 27,
1999, both of which are herein incorporated by reference in their
entirety.
A compound of Formula 1 may also be used with other agents useful
in treating abnormal cell growth or cancer, including, but not
limited to, agents capable of enhancing antitumor immune responses,
such as CTLA4 (cytotoxic lymphocite antigen 4) antibodies, and
other agents capable of blocking CTLA4; and anti-proliferative
agents such as other farnesyl protein transferase inhibitors, for
example the farnesyl protein transferase inhibitors described in
the references cited in the "Background" section, supra. Specific
CTLA4 antibodies that can be used in the present invention include
those described in U.S. Provisional Application 60/113,647 (filed
Dec. 23, 1998) which is herein incorporated by reference in its
entirety.
"Abnormal cell growth", as used herein, unless otherwise indicated,
refers to cell growth that is independent of normal regulatory
mechanisms (e.g., loss of contact inhibition). This includes the
abnormal growth of: (1) tumor cells (tumors) that proliferate by
expressing a mutated tyrosine kinase or overexpression of a
receptor tyrosine kinase; (2) benign and malignant cells of other
proliferative diseases in which aberrant tyrosine kinase activation
occurs; (4) any tumors that proliferate by receptor tyrosine
kinases; (5) any tumors that proliferate by aberrant
serine/threonine kinase activation; and (6) benign and malignant
cells of other proliferative diseases in which aberrant
serine/threonine kinase activation occurs.
The term "treating", as used herein, unless otherwise indicated,
means reversing, alleviating, inhibiting the progress of, or
preventing the disorder or condition to which such term applies, or
one or more symptoms of such disorder or condition. The term
"treatment", as used herein, unless otherwise indicated, refers to
the act of treating as "treating" is defined immediately above.
The term "halo", as used herein, unless otherwise indicated,
includes fluoro, chloro, bromo or iodo. Preferred halo groups are
fluoro and chloro.
The term "alkyl", as used herein, unless otherwise indicated,
includes saturated monovalent hydrocarbon radicals having straight,
cyclic (including mono- or multi-cyclic moieties) or branched
moieties. It is understood that for said alkyl group to include
cyclic moieties it must contain at least three carbon atoms.
The term "cycloalkyl", as used herein, unless otherwise indicated,
includes saturated monovalent hydrocarbon radicals having cyclic
(including mono- or multi-cyclic) moieties.
The term "alkenyl", as used herein, unless otherwise indicated,
includes alkyl groups, as defined above, having at least one
carbon-carbon double bond.
The term "alkynyl", as used herein, unless otherwise indicated,
includes alkyl groups, as defined above, having at least one
carbon-carbon triple bond.
The term "aryl", as used herein, unless otherwise indicated,
includes an organic radical derived from an aromatic hydrocarbon by
removal of one hydrogen, such as phenyl or naphthyl.
The term "alkoxy", as used herein, unless otherwise indicated,
includes --O-alkyl groups wherein alkyl is as defined above.
The term "4 to 12 membered heterocyclic", as used herein, unless
otherwise indicated, includes aromatic and non-aromatic
heterocyclic groups containing one or more heteroatoms each
selected from O, S and N, wherein each heterocyclic group has from
4 to 12 atoms in its ring system. Non-aromatic heterocyclic groups
include groups having only 4 atoms in their ring system, but
aromatic heterocyclic groups must have at least 5 atoms in their
ring system. The heterocyclic groups include benzo-fused ring
systems and ring systems substituted with one or more oxo moieties.
An example of a 4 membered heterocyclic group is azetidinyl
(derived from azetidine). An example of a 5 membered heterocyclic
group is thiazolyl and an example of a 10 membered heterocyclic
group is quinolinyl. Examples of non-aromatic heterocyclic groups
are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,
tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino,
thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl,
thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,
diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl,
3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,
1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl,
dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl,
imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl,
3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples
of aromatic heterocyclic groups are pyridinyl, imidazolyl,
pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl,
thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,
quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,
cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,
triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl,
thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,
benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,
naphthyridinyl, and furopyridinyl. The foregoing groups, as derived
from the compounds listed above, may be C-attached or N-attached
where such is possible. For instance, a group derived from pyrrole
may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). The
terms "5 to 12 membered heterocyclic", "5 to 6 membered
heterocyclic", and other uses of "heterocyclic", correspond to the
above definition with an appropriate number of ring members.
The term "Me" means methyl, "Et" means ethyl, and "Ac" means
acetyl.
In the definition of X.sup.1 above, the (CR.sup.4R.sup.5).sub.m and
(CR.sup.4R.sup.5).sub.n moieties of the foregoing X.sup.1 groups
optionally include one or two carbon-carbon double or triple bonds
where m or n are an integer from 2 to 4. This means that these
moieties may be, for instance, --C(R.sup.4).dbd.C(R.sup.5)-- where
n or m is 2, --C(R.sup.4).dbd.C(R.sup.5)CR.sup.4R.sup.5-- or
--CR.sup.4R.sup.5C(R.sup.4).dbd.C(R.sup.5)-- where m or n is 3,
--C.ident.C-- when m or n is 2, and so on.
The phrase "pharmaceutically acceptable salt(s)", as used herein,
unless otherwise indicated, includes salts of acidic or basic
groups which may be present in the compounds of the present
invention. The compounds of the present invention that are basic in
nature are capable of forming a wide variety of salts with various
inorganic and organic acids. The acids that may be used to prepare
pharmaceutically acceptable acid addition salts of such basic
compounds of are those that form non-toxic acid addition salts,
i.e., salts containing pharmacologically acceptable anions, such as
the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,
bisulfate, phosphate, acid phosphate, isonicotinate, acetate,
lactate, salicylate, citrate, acid citrate, tartrate, pantothenate,
bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,
gluconate, glucuronate, saccharate, formate, benzoate, glutamate,
methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate and pamoate [i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts. The compounds
of the present invention that include a basic moiety, such as an
amino group, may form pharmaceutically acceptable salts with
various amino acids, in addition to the acids mentioned above.
Those compounds of the present invention that are acidic in nature
are capable of forming base salts with various pharmacologically
acceptable cations. Examples of such salts include the alkali metal
or alkaline earth metal salts and, particularly, the calcium,
magnesium, sodium and potassium salts of the compounds of the
present invention.
When the compound of the present invention is acidic, its
corresponding salt can be conveniently prepared from
pharmaceutically acceptable non-toxic bases, including inorganic
bases and organic bases. Salts derived from such inorganic bases
include aluminum, ammonium, calcium, copper (ic and ous), ferric,
ferrous, lithium, magnesium, manganese (ic and ous), potassium,
sodium, zinc and the like salts. Particularly preferred are the
ammonium, calcium, magnesium, potassium and sodium slats. Salts
derived from pharmaceutically acceptable organic non-toxic bases
include salts of primary, secondary, and tertiary amines, as well
as cyclic amines and substituted amines such as naturally occurring
and synthesized substituted amines. Other pharmaceutically
acceptable organic non-toxic bases from which salts can be formed
include ion exchange resins such as, for example, arginine,
betaine, caffeine, choline, N',N'-dibenzylethylenediamine,
diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,
ethanolamine, ethylenediamine, N-ethylmorpholine,
N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine,
isopropylamine, lysine, methylglucamine, morpholine, piperazine,
piperidine, polyamine resins, procaine, purines, theobromine,
triethylameine, trimethylamine, tripropylamine, tromethamine and
the like.
When the compound of the present invention is basic, its
corresponding salt can be conveniently prepared from
pharmaceutically acceptable non-toxic acids, including inorganic
and organic acids. Such acids include, for example, acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,
p-toluenesulfonic acid and the like. Particularly preferred are
citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and
tartaric acids.
Certain functional groups contained within the compounds of the
present invention can be substituted for bioisosteric groups, that
is, groups which have similar spatial or electronic requirements to
the parent group, but exhibit differing or improved physicochemical
or other properties. Suitable examples are well known to those of
skill in the art, and include, but are not limited to moieties
described in Patini et al., Chem. Rev, 1996, 96, 3147-3176 and
references cited therein.
Compounds described herein contain one or more asymmetric centers
and may thus give rise to diastereomers and optical isomers. The
present invention includes all such possible diastereomers as well
as their racemic mixtures, their substantially pure resolved
enantiomers, all possible geometric isomers, and pharmaceutically
acceptable salts thereof. The above Formula I is shown without a
definitive stereochemistry at certain positions. The present
invention includes all optical isomers and stereoisomers of Formula
I, and mixtures thereof and pharmaceutically acceptable salts
thereof, and to all pharmaceutical compositions and methods of
treatment that may employ or contain them. Further, mixtures of
stereoisomers as well as isolated specific stereoisomers are also
included. During the course of the synthetic procedures used to
prepare such compounds, or in using racemization or epimerization
procedures known to those skilled in the art, the products of such
procedures can be a mixture of stereoisomers. The compounds of
Formula 1 may also exist as tautomers. This invention relates to
the use of all such tautomers and mixtures thereof.
The subject invention also includes isotopically-labelled
compounds, and the pharmaceutically acceptable salts or solvates
thereof, which are identical to those recited in Formula 1 but for
the fact that one or more atoms are replaced by an atom having an
atomic mass or mass number different from the atomic mass or mass
number usually found in nature. Examples of isotopes that can be
incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and
chlorine, such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.18O, .sup.17O .sup.35S, .sup.18F, and .sup.36Cl, respectively.
Compounds of the present invention and pharmaceutically acceptable
salts of said compounds which contain the aforementioned isotopes
and/or other isotopes of other atoms are within the scope of this
invention. Certain isotopically-labelled compounds of the present
invention, for example those into which radioactive isotopes such
as .sup.3H and .sup.14C are incorporated, are useful in drug and/or
substrate tissue distribution assays. Tritiated, i.e., .sup.3H, and
carbon-14, i.e., .sup.14C, isotopes are particularly preferred for
their ease of preparation and detectability. Further, substitution
with heavier isotopes such as deuterium, i.e., .sup.2H; can afford
certain therapeutic advantages resulting from greater metabolic
stability, for example increased in vivo half-life or reduced
dosage requirements and, hence, may be preferred in some
circumstances. Isotopically labelled compounds of Formula 1 of this
invention can generally be prepared by carrying out the procedures
disclosed in the Schemes and/or in the Examples and Preparations
below, by substituting a readily available isotopically labelled
reagent for a non-isotopically labelled reagent.
DETAILED DESCRIPTION OF THE INVENTION
The following general reaction schemes outline the synthetic routes
which may be used to prepare the compounds of the present
invention. In the Schemes below, substituents that correspond to
those used above with respect to the compound of Formula 1 are
defined as provided above unless otherwise indicated. The "Y"
substituents are used below where specific moieties are described
that do not correspond exactly to the defined variables used for
Formula 1 above but fall within the scope of the invention
described above.
1. Simple Benzimidazoles
Two preferred routes to these compounds are described below.
TABLE-US-00001 ##STR00003## ##STR00004##
In the above illustrated method A, reaction of the benzimidazole
core with a variety of electrophilic reagents can be carried out.
Examples of suitable electrophiles include acrylates and
propiolates (in conjunction with a suitable base, such as sodium
methoxide or potassium carbonate), or activated alcohol
derivatives, for example in a Mitsunobu type reaction. Amine
nucleophiles suitable for use in method B, step i include, but are
not limited to, .alpha.- or .beta.-amino acid derivatives in the
presence of an appropriate base, such as triethylamine, or
potassium carbonate. Suitable reducing conditions, such as those
employed in method A, step ii, or method B step ii are a reactive
metal catalyst, for example, palladium on carbon, Raney-nickel
etc., and a source of hydrogen (for example, the gaseous element,
or using transfer from materials such as hydrazine, ammonium
formate or cyclohexene). Other suitable reduction methods would be
readily apparent to those of skill in the art. In the above
illustrated method B, step iii, ring closure may be effected using
a variety of protocols, for example, where X.sup.4.dbd.H, an
orthoester such as triethylorthoformate may be used, or formamidine
acetate. Where X.sup.4 is alkyl, for example a methyl group, a
reagent such as acetic anhydride, or an acetamidine salt would be
suitable.
In the above illustrated methods A and B, hydrolysis of a
carboxylic acid ester may be accomplished using acidic (for
example, dilute hydrochloric acid) or basic (for example, dilute
sodium hydroxide) reaction conditions. In method A, regarding the
X.sup.1 moiety illustrated, R.sup.1 has been incorporated at C-1'
(i.e. m=0, n=1 in X.sup.1; --CHR.sup.1--CH.sub.2--CO.sub.2H). Other
compounds include those where m or n have other values including
analogues substituted at C-2' (i.e. m=1, n=0;
CH.sub.2--CHR.sup.1--CO.sub.2H).
2. 4-Substituted Benzimidazoles
A preferred route for preparing these analogues is shown below.
##STR00005##
Notes: HNY.sup.2Y.sup.3 is typically a cycloamine, e.g. piperidine;
X.sup.1 is as defined above.
The above illustrated reaction scheme utilises reaction conditions
that have been described previously, for example, nucleophilic
addition of a suitable amine, reduction, ring closure etc. Other
techniques familiar to those skilled in the art are referred to in
WO 97/10219.
3. Other Substituted Benzimidazoles
The following generic procedures are illustrative examples of
synthetic routes which are suitable for preparing the compounds
described in the current invention. Appropriate solvents,
temperatures and other experimental conditions are not specifically
stated, but would be readily apparent. While being representative,
the following procedures are not intended to be comprehensive, and
alternatives would be readily apparent to those of skill in the
art. For example, in Method C, the carboxylic acid group of
compound 14 could be replaced by a sulfonic acid, or suitable
derivative. Likewise, more heavily substituted benzimidazoles could
be prepared by utilisation of a more densely functionalised
starting material.
Starting chemicals, if not available from a commercial supplier can
be readily prepared according to procedures well known to those
skilled in the art.
##STR00006## ##STR00007##
In the above illustrated method A, reduction of the adduct derived
from compound 8 and the propiolate ester can be accomplished using
similar conditions to those already described. In the
transformation of compound 9 to 10, 12 to 13, 18 to 19 and 21 to 22
examples of suitable electrophiles (E.sup.+) could include (but are
not be limited to) reagents such as phenyl isocyanate (to form the
corresponding urea), phenyl thioisocyanate (thiourea), an activated
carboxylic acid derivative (activated using a reagent such as DCC,
or HATU, to form the corresponding amide), a sulfonyl chloride (to
form the corresponding sulfonamide), or using an in situ procedure
such as reductive amination (using an carbonyl species in
conjunction with a suitable reducing agent such as sodium
cyanoborohydride, to generate a homologated amine). FGI refers to
Functional Group Interconversions. Thus, a nitro-group within group
E in compounds 10 and 13 (for example) may be subsequently reduced
to an amino-group using conditions similar to those already
described. Further transformations can be carried out on the thus
generated amine, if so desired. Other suitable examples would be
readily apparent.
For the transformation of compounds 11 to 12, 14 to 15, 17 to 18,
20 to 21 and 23 to 24 suitable conditions have already been
outlined for the nucleophilic addition of an amine, reduction, and
ring closure steps.
In compound 15, AG refers to an activating group for a carboxylic
acid, such that it may undergo a ready displacement reaction with a
suitable nucleophile (Nu.sup.-). Examples of activating protocols
are numerous, and include (but are not limited to), conversion to
the corresponding carboxylic acid chloride (or other halide),
reaction with reagents such as DCC, HATU etc. Suitable nucleophiles
include (but are not limited to) primary and secondary amines,
thiols, alcohols, phenols, thiophenols etc. Other examples would be
readily apparent. A reference that relates to compounds of the
structure 15 or 16 is German patent DD 123,466 (Dec. 20, 1976).
In the above illustrated method F, the conversion of compound 24 to
25 is representative of classes of reactions that are well known to
occur with suitable aryl halides and suitable coupling partners,
including (but not limited to) boronic acids, trialkylstannanes,
and amines (aliphatic and aromatic), under catalysis by an
appropriate transition metal catalyst, such as
tetrakistriphenylphosphine palladium (0). Other reactions of this
type, coupling partners and catalysts would be readily
apparent.
In principle, Method C could be used to prepare the analogous
6-carboxylic acid isomers, and the corresponding 5- and
6-sulfonamido-substituted compounds, by judicious choice of
starting material.
The compounds of the present invention may have asymmetric carbon
atoms. Diasteromeric mixtures can be separated into their
individual diastereomers on the basis of their physical chemical
differences by methods known to those skilled in the art, for
example, by chromatography or fractional crystallization.
Enantiomers can be separated by converting the enantiomeric
mixtures into a diastereomric mixture by reaction with an
appropriate optically active compound (e.g., alcohol), separating
the diastereomers and converting (e.g., hydrolyzing) the individual
diastereomers to the corresponding pure enantiomers. All such
isomers, including diastereomeric mixtures and pure enantiomers are
considered as part of the invention.
The compounds of Formula 1 that are basic in nature are capable of
forming a wide variety of different salts with various inorganic
and organic acids. Although such salts must be pharmaceutically
acceptable for administration to animals, it is often desirable in
practice to initially isolate the compound of Formula 1 from the
reaction mixture as a pharmaceutically unacceptable salt and then
simply convert the latter back to the free base compound by
treatment with an alkaline reagent and subsequently convert the
latter free base to a pharmaceutically acceptable acid addition
salt. The acid addition salts of the base compounds of this
invention are readily prepared by treating the base compound with a
substantially equivalent amount of the chosen mineral or organic
acid in an aqueous solvent medium or in a suitable organic solvent,
such as methanol or ethanol. Upon careful evaporation of the
solvent, the desired solid salt is readily obtained. The desired
acid salt can also be precipitated from a solution of the free base
in an organic solvent by adding to the solution an appropriate
mineral or organic acid.
Those compounds of Formula 1 that are acidic in nature are capable
of forming base salts with various pharmacologically acceptable
cations. Examples of such salts include the alkali metal or
alkaline-earth metal salts and particularly, the sodium and
potassium salts. These salts are all prepared by conventional
techniques. The chemical bases which are used as reagents to
prepare the pharmaceutically acceptable base salts of this
invention are those which form non-toxic base salts with the acidic
compounds of Formula 1. Such non-toxic base salts include those
derived from such pharmacologically acceptable cations as sodium,
potassium calcium and magnesium, etc. These salts can easily be
prepared by treating the corresponding acidic compounds with an
aqueous solution containing the desired pharmacologically
acceptable cations, and then evaporating the resulting solution to
dryness, preferably under reduced pressure. Alternatively, they may
also be prepared by mixing lower alkanolic solutions of the acidic
compounds and the desired alkali metal alkoxide together, and then
evaporating the resulting solution to dryness in the same manner as
before. In either case, stoichiometric quantities of reagents are
preferably employed in order to ensure completeness of reaction and
maximum yields of the desired final product. Since a single
compound of the present invention may include more than one acidic
or basic moieties, the compounds of the present invention may
include mono, di or tri-salts in a single compound.
The compounds of the present invention are potent inhibitors of the
integrin family of transmembrane receptors involved in cell
adhesion, and thus are all adapted to therapeutic use as
anti-angiogenic agents (e.g., disorders characterised by
inappropriate vascularisation, for example tumour associated
angiogenesis which is a pre-requisite for tumour cell growth,
proliferation and metastasis) in mammals, particularly in humans.
In particular, the compounds of the present invention are useful in
the prevention and treatment of a variety of human
hyperproliferative disorders such as malignant and benign tumors of
the liver, kidney, bladder, breast, gastric, ovarian, colorectal,
prostate, pancreatic, lung, vulval, thyroid, hepatic carcinomas,
sarcomas, glioblastomas, head and neck, and other hyperplastic
conditions such as benign hyperplasia of the skin (e.g., psoriasis)
and benign hyperplasia of the prostate (e.g., BPH). It is, in
addition, expected that a compound of the present invention may
possess activity against a range of leukemias and lymphoid
malignancies.
The activity of the compounds of Formula 1 may be determined by the
following procedures.
Assays to Measure Integrin/Ligand Interactions
.alpha..sub.v.beta..sub.3, .alpha..sub.v.beta..sub.5/Vitronectin
Binding Assays
Human .alpha..sub.v.beta..sub.3 was purified from extracts of
placenta tissue based on affinity chromatography techniques
employing monoclonal antibody LM609 [Pytela et al., Methods
Enzymol. (1987), 144, 475-489; Smith and Cheresh, J. Biol. Chem.,
(1988), 263, 18726-18731]. The purified integrin was aliquoted and
stored at -70.degree. C. in PBS containing 0.1% NP-40 and 2 mM
CaCl.sub.2. Twelve to twenty-four hours prior to compound testing,
an aliquot was thawed and diluted to 0.3 .mu.g/mL protein in
"binding buffer," a buffer composed of 50 mM Tris-HCl, pH 7.4,
containing 100 mM NaCl, 1 mM CaCl.sub.2, 1 mM MgCl.sub.2 and 1 mM
MnCl.sub.2. Alternatively, a "low Mn.sup.2+" binding buffer
containing 0.002 mM MnCl.sub.2 was used, in order to assess
vitronectin binding to .alpha..sub.v.beta..sub.3 in an altered
conformation state [e.g. Smith et al., J. Biol. Chem., (1994), 269,
960-967; Kirchhofer et al., J. Biol. Chem., (1990), 265,
18525-18530]. 100 .mu.L Of the diluted .alpha..sub.v.beta..sub.3
protein was added to wells of the assay plates (Falcon.TM. Pro-Bind
96-well polystyrene plates; Becton Dickinson, Inc., Franklin Lakes,
N.J.). Wells D1 to D6 received binding buffer only, and served as
control wells for the assessment of nonspecific binding of the
vitronectin and/or reporter antibody. Plates were incubated at
4.degree. C. for 12 to 24 hours, at which time wells were aspirated
completely. The wells were washed once with 250 .mu.L of binding
buffer containing 0.04% Tween-20 (binding buffer/Tween-20; ICN
Biomedicals, Inc., Aurora, Ohio), followed by the addition of 250
.mu.L per well of a blocking solution composed of binding
buffer/Tween-20 containing 1% casein (Sigma Chemical Co., St.
Louis, Mo.). The blocking solution is prepared at least 12 hours
prior to use, to allow for complete dissolution of the casein.
After incubation of the plates at room temperature for 1 hour,
wells were aspirated and washed twice with 250 .mu.L binding
buffer/Tween-20. The wells were then aspirated completely and 40
.mu.L of binding buffer/Tween-20 was added prior to compound
addition.
Compounds were resuspended in 100% DMSO to yield stock
concentrations of 1 to 10 mM. A compound plate was prepared by
adding 10 .mu.L of the stock compounds to 190 .mu.L of deionized
water, in duplicate wells of a 96-well U-bottom plate (Falcon.TM.
3910). One row was reserved for each compound (six concentrations
in duplicates), except for row D, which contained 5% DMSO/95% water
only. One-to-four-fold serial dilutions were prepared by
transferring 50 .mu.L of the first well concentration to 150 .mu.L
of 5% DMSO/95% water in the adjacent two wells. After completion of
the various dilutions of the compounds in the compound plates, 10
.mu.L of each compound solution was transferred to the
corresponding wells in the assay plates containing 40 .mu.L binding
buffer/Tween-20.
Human vitronectin from plasma (Collaborative Biomedical Products,
Bedford, Mass.) was resuspended at 0.5 mg/ml in binding
buffer/Tween-20, for 12 to 18 hours at room temperature without
stirring. Aliquots were prepared and frozen at -70.degree. C.
Aliquots were thawed as needed and the vitronectin was diluted to
50 ng/mL in binding buffer/Tween-20. 50 .mu.L of this solution was
then transferred to assay plates containing integrin and the
various dilutions of compounds. Assay plates were incubated at room
temperature for 15 minutes to allow vitronectin binding in the
presence or absence of compounds. Wells were washed extensively (6
times) with 250 .mu.L binding buffer/Tween-20 and aspirated. To
detect the bound vitronectin, a horseradish peroxidase
(HRP)-conjugated, sheep anti-vitronectin antibody (K90111B,
Biodesign International, Kennebunk, Me.) was diluted 1:2000 in
binding buffer/Tween-20 containing 2% BSA (Sigma, St. Louis, Mo.).
100 .mu.L Of antibody solution was transferred to each well in the
assay plates, followed by incubation at room temperature for 90
minutes and 6.times. washing with 250 .mu.L binding
buffer/Tween-20. After the final wash, wells were aspirated
completely. The bound anti-vitronectin conjugate was detected by
adding 100 .mu.L of TMB peroxidase substrate solution (Kirkegaard
and Perry Laboratories, Gaithersburg, Md.). Color development was
stopped after 20 minutes by the addition of 100 .mu.L of 0.18 M
H.sub.2SO.sub.4. The colorimetric signal was quantitated at a
wavelength of 450 nm using an EL340 Bio Kinetics Reader (Bio-Tek
Instruments, Inc). The IC.sub.50 (concentration of the compound to
inhibit 50% of the specific binding of vitronectin to integrin) and
standard errors were determined by a nonlinear, least squares curve
fitting routine.
Interactions between a second vitronectin receptor, integrin
.alpha..sub.v.beta..sub.5 [Smith et al., J. Bio. Chem., (1990),
265, 11008-11013] and vitronectin were measured using the same
assay format utilized for .alpha..sub.v.beta..sub.3. Purified human
.alpha..sub.v.beta..sub.5 (octyl-.beta.-D-glucopyranoside
formulation) was obtained from Chemicon International, Inc.
(Temecula, Calif.) and diluted in binding buffer. Most experiments
utilized integrin .alpha..sub.v.beta..sub.5 at a concentration of
0.6 .mu.g/mL, which produced a vitronectin-binding signal roughly
equivalent to .alpha..sub.v.beta..sub.3 at 0.3 .mu.g/mL.
Purification of Human .alpha..sub.IIb.beta..sub.3 (GPIIb-IIIa).
Ten units of outdated platelets were purchased from Long Island
Blood Services (Melville, N.Y.). The platelets were pelleted and
washed three times in 20 mM Tris-HCl, pH 7.2, containing 150 mM
NaCl and 1 mM EDTA. Pelleted platelets could be frozen at
-70.degree. C. until needed. The equivalent of 5 units was thawed
and suspended in a lysis buffer composed of 20 mM Tris-HCl, pH 7.4,
containing 140 mM NaCl, 2 mM CaCl.sub.2 and 3% octylglucoside. The
platelet lysate was gently stirred for 2 hours at 4.degree. C.
followed by centrifugation at 100,000.times.g for one hour at
4.degree. C. in a Beckman SW28 rotor. A lectin gel (5 mL) composed
of purified Lens culinaris lectin covalently linked to agarose
beads (E-Y Laboratories, Inc., San Mateo, Calif.) was equilibrated
with equilibration buffer (composed of 20 mM Tris-HCl, pH 7.4,
containing 100 mM NaCl, 2 mM CaCl.sub.2 and 1% octylglucoside). The
platelet lysate was gently stirred with the lectin gel for 2 hours
at 4.degree. C. The mixture was poured into a column, which was
washed with 100 mL of the equilibration buffer. The bound
.alpha..sub.IIb.beta..sub.3 was eluted, first with equilibration
buffer containing 10% dextrose, followed by equilibration buffer
containing 0.1M D-mannose. Fractions that were >75% pure, as
estimated on silver stained gels, were pooled and dialyzed versus
phosphate buffered saline (PBS) containing 1 mM CaCl.sub.2, 1 mM
MnCl.sub.2 and 0.1% NP-40. Aliquots were stored at -70.degree. C.
until needed.
.alpha..sub.IIb.beta..sub.3/Fibrinogen Binding Assay.
An ELISA to measure interactions between integrin
.alpha..sub.IIb.beta..sub.3 and fibrinogen was established by
coating 96-well, flat-bottom EIA/RIA plates from Costar.TM.
(Corning, Inc., Corning, N.Y.) with 200 ng of purified
.alpha..sub.IIb.beta..sub.3 in 100 .mu.L of binding buffer, for 12
to 18 hours at 37.degree. C. Coated plates were subsequently
washed, blocked, aspirated and re-washed as described previously
for the .alpha..sub.v.beta..sub.3 ELISA. Locations of control wells
and compound addition steps were also the same as described
previously for the .alpha..sub.v.beta..sub.3 ELISA. Human
fibrinogen, depleted of plasminogen, was purchased from Calbiochem
(San Diego, Calif.) and biotinylated using a commercial kit
(EZ-Link.TM. Sulfo-NHS-LC) from Pierce (Rockford, Ill.).
Biotin-fibrinogen was diluted to 100 ng/mL in binding
buffer/Tween-20, and 50 .mu.L/well was added to the compound plates
coated with .alpha..sub.IIb.beta..sub.3 in the presence or absence
of compounds. The subsequent incubation and wash steps were the
same as described previously for the .alpha..sub.v.beta..sub.3
ELISA. Bound biotin-fibrinogen was detected by the addition of 100
.mu.L/well of streptavidin that was conjugated to HRP (Jackson
ImmunoResearch Laboratories, Inc., West Grove, Pa.). The
streptavidin-HRP conjugate was used at 250 ng/mL in binding
buffer/Tween-20 containing 2% BSA. The subsequent incubation, wash
and development steps were the same as described previously for the
.alpha..sub.v.beta..sub.3 ELISA.
Cell Adhesion Assays
Short-Term Assays.
Assays to measure cell adhesion to extracellular matrix proteins in
the presence or absence of compounds were conducted using both
immortalized and primary human cells. The melanoma lines G-361 and
A2058 were obtained from the American Type Culture Collection
(ATCC, Rockville, Md.). The G-361 line was maintained in McCoy's 5A
Medium (16600-082, GibcoBRL) supplemented with 10% fetal calf serum
(FCS), and L-glutamine; the A2058 line was maintained in DMEM
Medium (11960-044, Gibco BRL) supplemented with 10% fetal calf
serum (FCS), and L-glutamine. Primary human umbilical vein
endothelial cells (HUVEC) from pooled donors were obtained from
Clonetics (San Diego, Calif.). HUVEC cultures were maintained and
passaged on schedules recommended by Clonetics.
Cell adhesion assays were performed using 96-well, flat-bottom,
non-tissue culture-treated plates (9050, Costar.TM., Corning, Inc.,
Corning, N.Y.). The wells received 100 .mu.L of PBS containing
vitronectin (Collaborative Biomedical Products) at 1 .mu.g/mL or
fibronectin (GibcoBRL, Rockville, Md.) at 2 .mu.g/mL, for 12 to 18
hours at 4.degree. C. Wells D1 to D6 received PBS alone, and served
as control wells to measure nonspecific attachment of cells to
untreated plastic. Wells were aspirated, washed once with 250 .mu.L
PBS, and blocked with 250 .mu.L of PBS containing 2% BSA, for 2
hours at room temperature. The wells were aspirated, and received
250 .mu.L of adhesion buffer, composed of Hepes-Buffered Saline
Solution (HBSS, Clonetics) containing 1% BSA, 1 mM CaCl.sub.2, 1 mM
MgCl.sub.2 and 2 mM MnCl.sub.2. The wells were aspirated completely
and 40 .mu.L of adhesion buffer was added, followed by the addition
of various dilutions of compounds in 5% DMSO/95% water. During the
plate-blocking step, human cells were washed once with PBS,
followed by gentle detachment with sterile PBS containing 10 mM
EDTA. Detached cells were counted, pelleted, and gently resuspended
at one million cells per mL in warm adhesion buffer. 50 .mu.L Of
the cell suspension (fifty thousand cells) was added to the plates
containing compounds, and plates were transferred to a 37.degree.
C. incubator for 1 hour. Subsequently, the unattached cells were
removed by one gentle wash of 300 .mu.L/well warm cell media
lacking fetal calf serum, followed by the addition of 100
.mu.L/well warm cell media lacking fetal calf serum. 25 .mu.L Of
PBS containing 2 mg/mL MTT
(3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide;
Sigma) was added, and plates were returned to the 37.degree. C.
incubator for 1 to 11/2 hours. Wells were aspirated, and the
metabolized MTT formazan product was solubilized with 100 .mu.L of
ethanol/acetone (50%/50%). Plates were read at 540 nM in an EL340
Bio Kinetics Reader (Bio-Tek Instruments, Inc); the mean absorbance
from control wells (D1-D6) was subtracted, and cell adhesion
relative to the control wells lacking compounds (D7-D12) was
plotted.
Long-Term Adhesion, Growth and Survival Assays.
The short-term adhesion assay (one-hour co-incubation of cells with
compounds) could be adapted to assays that measure longer-term (5
to 48 hours) effects of compounds on the adhesion, growth and/or
survival of cells seeded onto various ECM proteins. For assays
using MTT as the readout, compound evaluations were conducted
similarly to the one-hour assays with several modifications. First,
only HUVEC cells were utilized, and each well was seeded with
17,000 cells instead of 50,000. Second, the adhesion buffer was
substituted with regular growth medium to support the growth and
survival of adhering HUVEC over extended time periods.
Administration of the compounds of the present invention
(hereinafter the "active compound(s)") can be affected by any
method that enables delivery of the compounds to the site of
action. These methods include oral routes, intraduodenal routes,
parenteral injection (including intravenous, subcutaneous,
intramuscular, intravascular or infusion), topical, and rectal
administration. The compound represented by Formula I, or a
pharmaceutically acceptable salt thereof, may also be administered
by controlled release means and/or delivery devices.
The amount of the active compound administered will be dependent on
the subject being treated, the severity of the disorder or
condition, the rate of administration, the disposition of the
compound and the discretion of the prescribing physician. However,
an effective dosage is in the range of about 0.001 to about 100 mg
per kg body weight per day, preferably about 1 to about 35
mg/kg/day, in single or divided doses. For a 70 kg human, this
would amount to about 0.05 to about 7 g/day, preferably about 0.2
to about 2.5 g/day. In some instances, dosage levels below the
lower limit of the aforesaid range may be more than adequate, while
in other cases still larger doses may be employed without causing
any harmful side effect, provided that such larger doses are first
divided into several small doses for administration throughout the
day.
The active compound may be applied as a sole therapy or may involve
one or more other anti-tumour substances, for example those
selected from, for example, mitotic inhibitors, for example
vinblastine; alkylating agents, for example cis-platin, carboplatin
and cyclophosphamide; anti-metabolites, for example 5-fluorouracil,
cytosine arabinoside and hydroxyurea, or, for example, one of the
preferred anti-metabolites disclosed in European Patent Application
No. 239362 such as
N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]--
2-thenoyl)-L-glutamic acid; growth factor inhibitors; cell cycle
inhibitors; intercalating antibiotics, for example adriamycin and
bleomycin; enzymes, for example interferon; and anti-hormones, for
example anti-estrogens such as Nolvadex.TM. (tamoxifen) or, for
example anti-androgens such as Casodex.TM.
(4'-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'-(trifluoromet-
hyl)propionanilide). Such conjoint treatment may be achieved by way
of the simultaneous, sequential or separate dosing of the
individual components of the treatment.
The pharmaceutical composition may, for example, be in a form
suitable for oral administration such as a tablet, capsule,
cachets, pill, powder, granules, sustained release formulations,
solution, as a suspension in an aqueous liquid, as a non-aqueous
liquid, as an oil-in-water emulsion, as a water-in-oil liquid
emulsion, for parenteral injection as a sterile solution,
suspension or emulsion, for topical administration as an ointment
or cream or for rectal administration as a suppository. The
pharmaceutical composition may be in unit dosage forms suitable for
single administration of precise dosages. The pharmaceutical
composition will include a conventional pharmaceutical carrier or
excipient and one or more of the compound according to the
invention as an active ingredient. In addition, it may include
other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
Optionally, tablets, capsules, or pills may be coated by standard
aqueous or nonaqueous techniques.
Exemplary parenteral administration forms include solutions or
suspensions of active compounds in sterile aqueous solutions, for
example, aqueous propylene glycol or dextrose solutions. Such
dosage forms can be suitably buffered, if desired.
Suitable pharmaceutical carriers include, for example, a solid,
liquid, or gas, such as inert diluents or fillers, water and
various organic solvents. The pharmaceutical compositions may, if
desired, contain additional ingredients such as flavorings,
binders, excipients and the like. Thus for oral administration,
tablets containing various excipients, such as citric acid, may be
employed together with various disintegrants such as starch,
alginic acid and certain complex silicates and with binding agents
such as sucrose, gelatin and acacia. Additionally, lubricating
agents such as magnesium stearate, sodium lauryl sulfate,
hydroxypropylcellulose, and talc are often useful for tableting
purposes. Solid compositions of a similar type may also be employed
in soft and hard filled gelatin capsules. Preferred materials,
therefor, include lactose or milk sugar and high molecular weight
polyethylene glycols. When aqueous suspensions or elixirs are
desired for oral administration the active compound therein may be
combined with various sweetening or flavoring agents, coloring or
dyes and emulsifying agents or suspending agents, together with
diluents such as water, ethanol, propylene glycol, glycerin, or
combinations thereof Examples of solid carriers include lactose,
terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium
stearate, and stearic acid. Examples of liquid carriers are sugar
syrup, peanut oil, olive oil, and water. Examples of gaseous
carriers include carbon dioxide and nitrogen.
A tablet containing the composition of this invention may be
prepared by compression or molding, optionally with one or more
accessory ingredients or adjuvants. Compressed tablets may be
prepared by compressing, in a suitable machine, the active
ingredient in a free-flowing form such as powder or granules,
optionally mixed with a binder, lubricant, inert diluent, surface
active or dispersing agent. Molded tablets may be made by molding
in a suitable machine, a mixture of the powdered compound moistened
with an inert liquid diluent. Each tablet preferably contains from
about 0.05 mg to about 5 g of the active ingredient and each cachet
or capsule preferably containing from about 0.05 mg to about 5 g of
the active ingredient.
For example, a formulation intended for the oral administration to
humans may contain from about 0.5 mg to about 5 g of active agent,
compounded with an appropriate and convenient amount of carrier
material which may vary from about 5 to about 95 percent of the
total composition. Unit dosage forms will generally contain between
from about 1 mg to about 2 g of the active ingredient, typically 25
mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg,
1000 mg.
Pharmaceutical compositions of the present invention suitable for
parenteral administration may be prepared as solutions or
suspensions of the active compounds in water. A suitable surfactant
can be included such as, for example, hydroxypropylcellulose.
Dispersions can also be prepared in glycerol, liquid polyethylene
glycols, and mixtures thereof in oils. Further, a preservative can
be included to prevent the detrimental growth of
microorganisms.
Pharmaceutical compositions of the present invention suitable for
injectable use include sterile aqueous solutions or dispersions.
Furthermore, the compositions can be in the form of sterile powders
for the extemporaneous preparation of such sterile injectable
solutions or dispersions. In all cases, the final injectable form
must be sterile and must be effectively fluid for easy
syringability. The pharmaceutical compositions must be stable under
the conditions of manufacture and storage; thus, preferably should
be preserved against the contaminating action of microorganisms
such as bacteria and fungi. The carrier can be a solvent or
dispersion medium containing, for example, water, ethanol, polyol
(e.g., glycerol, propylene glycol and liquid polyethylene glycol),
vegetable oils, and suitable mixtures thereof.
Pharmaceutical compositions of the present invention can be in a
form suitable for topical use such as, for example, an aerosol,
cream, ointment, lotion, dusting powder, or the like. Further, the
compositions can be in a form suitable for use in transdermal
devices. These formulations may be prepared, utilizing a compound
represented by Formula 1 of this invention, or a pharmaceutically
acceptable salt thereof, via conventional processing methods. As an
example, a cream or ointment is prepared by admixing hydrophilic
material and water, together with about 5 wt % to about 10 wt % of
the compound, to produce a cream or ointment having a desired
consistency.
Pharmaceutical compositions of this invention can be in a form
suitable for rectal administration wherein the carrier is a solid.
It is preferable that the mixture forms unit dose suppositories.
Suitable carriers include cocoa butter and other materials commonly
used in the art. The suppositories may be conveniently formed by
first admixing the composition with the softened or melted
carrier(s) followed by chilling and shaping in molds.
In addition to the aforementioned carrier ingredients, the
pharmaceutical formulations described above may include, as
appropriate, one or more additional carrier ingredients such as
diluents, buffers, flavoring agents, binders, surface-active
agents, thickeners, lubricants, preservatives (including
anti-oxidants) and the like. Furthermore, other adjuvants can be
included to render the formulation isotonic with the blood of the
intended recipient. Compositions containing a compound described by
Formula 1, or pharmaceutically acceptable salts or solvates
thereof, may also be prepared in powder or liquid concentrate
form.
Generally, dosage levels on the order of from about 0.01 mg/kg to
about 150 mg/kg of body weight per day are useful in the treatment
of the above-indicated conditions, or alternatively about 0.5 mg to
about 7 g per patient per day. For example, abnormal cell growth
may be effectively treated by the administration of from about 0.01
to 50 mg of the compound per kilogram of body weight per day, or
alternatively about 0.5 mg to about 3.5 g per patient per day.
It is understood, however, that the specific dose level for any
particular patient will depend upon a variety of factors including
the age, body weight, general health, sex, diet, time of
administration, route of administration, rate of excretion, drug
combination and the severity of the particular disease undergoing
therapy.
Methods of preparing various pharmaceutical compositions with a
specific amount of active compound are known, or will be apparent,
to those skilled in this art. For examples, see Remington's
Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th
Edition (1975).
The examples and preparations provided below further illustrate and
exemplify the compounds of the present invention and methods of
preparing such compounds. It is to be understood that the scope of
the present invention is not limited in any way by the scope of the
following examples and preparations. In the following examples
molecules with a single chiral center, unless otherwise noted,
exist as a racemic mixture. Those molecules with two or more chiral
centers, unless otherwise noted, exist as a racemic mixture of
diastereomers. Single enantiomers/diastereomers may be obtained by
methods known to those skilled in the art.
The present invention is further illustrated by, but not limited in
scope to, the following examples and preparations.
ABBREVIATIONS
DMAP N,N-dimethylaminopyridine DMF N,N-Dimethylformamide DMSO
Dimethylsulfoxide HATU
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate LCMS Liquid Chromatography/Mass Spectometry NMP
N-Methylpyrrolidinone NMR Nuclear magnetic resonance RP-HPLC
Reverse Phase High Pressure Liquid Chromatography TBTU
O-(1H-Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate Compound Numbering
Compounds are numbered according to the relevant procedure [i.e.
Compound 25b corresponds to the compound prepared in Procedure 25,
Part (b)]. Compounds synthesised as part of combinatorial libraries
are assigned a code of type Lx, where L denotes "Library" and x is
the compound number.
Details for Experimental Procedures of Discrete Examples
Reverse phase, high pressure liquid chromatography used in the
following preparations was effected according to the following
general method. A HiChrom column (C18 silica packing, 5 micron
particle size, 20.times.100 mm; AnaChem), was previously
equilibrated in a mixture of water, acetonitrile, and
trifluoroacetic acid (100:100:0.1) at pH 3.0. Samples were eluted
using a linear gradient of 20 to 80% acetonitrile in water,
containing 0.1% trifluroacetic acid, at pH 3.0, over 20 minutes,
with a flow rate of 10 mLmin.sup.-1. Analysis was undertaken at 220
nm using a diode array detector.
Where a compound was isolated in the final instance by evaporation
from aqueous hydrochloric acid, this was assumed to afford the
compound as its corresponding hydrochloride salt. Likewise, where a
compound was purified by RP-HPLC using a trifluoroacetic acid
buffered mobile phase, it was assumed to be isolated as its
trifluoroacetate salt. Salt equivalence was not determined for
compounds.
Analytical Procedures
.sup.1H NMR analysis was conducted on a Varian Gemini instrument at
400 MHz, using standard-procedures.
LCMS analysis was performed using a Gilson 215 autosampler and
Gilson 819 autoinjector, attached to a Hewlett Packard HP110. Mass
spectra were obtained on a Micromass Platform LC mass spectrometer,
using positive and negative electrospray ionisation. Masses found
refer to the most abundant MH.sup.+ positive ion found
corresponding to title compound, unless otherwise stated.
The following general methods were used: Method A: HiChrom RP3
column (5 micron, 3.2.times.100 mm), 7.5 minute gradient or Method
B: Supelco Discovery C18 (5 micron, 4.6.times.50 mm), 4.8 minute
gradient or Method C: Waters Symmetry C18 (5 micron, 2.1.times.30
mm), 3.5 minute gradient
Samples were eluted using a linear gradient of 0-100% Solvent B in
Solvent A over either 4.8 or 7.5 minutes (see above). The buffer
used was either formic acid (0.1%) or ammonium acetate (10 mM). The
buffer used was observed to have no noticeable effect on sample
retention time.
Mobile Phase I: (plus buffer) Solvent A: Water (95%), acetonitrile
(5%). Solvent B: Acetonitrile (100%).
Mobile Phase II: (plus buffer) Solvent A: Water (95%), methanol
(5%). Solvent B: Methanol (100%).
Preparation 1
(a) Methyl 3-(5-nitro-1H-benzimidazol-1-yl)butanoate and methyl
3-(6-nitro-1H-benzimidazol-1-yl)butanoate
##STR00008##
To a solution of 5-nitrobenzimidazole (250 mg, 1.53 mmol) in dry
methanol (10 mL) was added methyl crotonate (325 .mu.L, 3.06 mmol)
and sodium methoxide (35 .mu.L of a 25 wt % solution in methanol,
153 .mu.mol), and the resulting solution heated to reflux for 48
hours. The solution was then evaporated in vacuo to afford the
title compound as a ca. 1:1 mixture of regioisomers (as determined
by .sup.1H NMR), .sup.1H NMR: (CDCl.sub.3) of the mixture, 8.65 (d,
J=2.20), 8.43 (d, J=2.20), 8.25-8.14 (m), 7.81 (d, J=8.79), 7.55
(d, J=9.16), 5.09-5.01 (m), 3.59 (s), 3.58 (s), 3.06-2.87 (m), 1.73
(d, J=6.96), 1.71 (d, J=6.96).
(b) Methyl 3-(5-amino-1H-benzimidazol-1-yl)butanoate & methyl
3-(6-amino-1H-benzimidazol-1-yl)butanoate
##STR00009##
To a solution of the mixture of methyl
3-(5-nitro-1H-benzimidazol-1-yl)butanoate & methyl
3-(6-nitro-1H-benzimidazol-1-yl)butanoate (400 mg, 1.52 mmol, ca.
1:1 mixture) in methanol (10 mL) was added palladium on carbon (100
mg, 10% w/w Pd). The suspension was then stirred under an
atmosphere of hydrogen for 110 hours. The suspension was filtered,
evaporated in vacuo, and the residue purified by flash column
chromatography on silica gel, eluting with a mixture of
dichloromethane and methanol (97:3 to 9:1). This gave, in order of
elution, methyl 3-(5-amino-1H-benzimidazol-1-yl)butanoate (91 mg),
[LCMS (Method A, Mobile Phase II) RT=3.24 min, MH.sup.+ 234];
methyl 3-(6-amino-1H-benzimidazol-1-yl)butanoate (78 mg), [LCMS
(Method A, Mobile Phase II) RT=3.38 min, MH.sup.+ 234].
Example 1c
3-(5-Amino-1H-benzimidazol-1-yl)butanoic acid
##STR00010##
A solution of methyl 3-(5-amino-1H-benzimidazol-1-yl)butanoate (91
mg, 390 .mu.mol) in hydrochloric acid (5 mL of a 5N solution) was
stirred at room temperature for 163 hours. The solution was then
evaporated in vacuo to afford the title compound, [LCMS (Method A,
Mobile Phase II) RT=1.54 min, MH.sup.+ 220].
(d) Example 1d
3-(6-Amino-1H-benzimidazol-1-yl)butanoic acid
##STR00011##
A solution of methyl 3-(6-amino-1H-benzimidazol-1-yl)butanoate (78
mg, 334 .mu.mol) in hydrochloric acid (5 mL of a 5N solution) was
stirred at room temperature for 163 hours. The solution was then
evaporated in vacuo to afford the title compound, [LCMS (Method A,
Mobile Phase II) RT=1.53 min, MH.sup.+ 220].
Example 2
(a) Ethyl-3-(5-nitro-1H-benzimidazol-1-yl)-3-phenyl-2-propenoate
&
ethyl-3-(6-nitro-1H-benzimidazol-1-yl)-3-phenyl-2-propenoate
##STR00012##
To a solution of 5-nitrobenzimidazole (3.00 g, 18.4 mmol) in DMF
(60 mL) was added ethyl phenylpropiolate (3.34 mL, 20.2 mmol) and
potassium carbonate (2.80 g, 20.3 mmol). The suspension was then
heated to 110.degree. C., and stirred for 20 hours. The suspension
was evaporated to dryness in vacuo, and the residue was purified by
flash column chromatography on silica gel, eluting with a mixture
of dichloromethane and methanol (95:5), to give a mixture of the
title compounds. [LCMS (Method A, II) RT=5.70 and 5.80 min
respectively, MH.sup.+ 338].
(b) Ethyl 3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate &
ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate
##STR00013##
To a mixture of
ethyl-3-(5-nitro-1H-benzimidazol-1-yl)-3-phenyl-2-propenoate and
ethyl-3-(6-nitro-1H-benzimidazol-1-yl)-3-phenyl-2-propenoate (5.34
g, 15.8 mmol) in a mixture of ethanol and water (10:1, 66 mL) was
added palladium on carbon (801 mg, 10% w/w Pd) and ammonium formate
(6.0 g, 95 mmol). The suspension was heated to reflux, and was
stirred at this temperature for 1.5 hours. The reaction mixture was
allowed to cool to room temperature, then filtered through
Celite.RTM., and the filter pad washed several times with ethanol.
The combined filtrates were evaporated in vacuo, and the residue
was purified by flash column chromatography on silica gel, eluting
with a mixture of dichloromethane and methanol (99:1) to give, in
order of elution, ethyl
3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate, [LCMS (Method
A, Mobile Phase I) RT=3.33 min, MH.sup.+ 310] and ethyl
3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (1.96 g), [LCMS
(Method A, Mobile Phase I) RT=3.35 min, MH.sup.+ 310].
(c) Example 2c
3-(5-Amino-1H-benzimidazol-1-yl)-3-phenylpropanoic acid
##STR00014##
A solution of ethyl
3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (40 mg, 129
.mu.mol) in hydrochloric acid (20 mL of a 5N solution) was stirred
at room temperature for 72 hours. The solution was evaporated in
vacuo and purified by RP-HPLC to afford the title compound, [LCMS
(Method A, Mobile Phase II) RT=2.61 min, MH.sup.+ 282].
(d) 3-(6-Amino-1H-benzimidazol-1-yl)-3-phenylpropanoic acid
##STR00015##
A solution of ethyl
3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate, (25 mg, 81
.mu.mol) in hydrochloric acid (20 mL of a 5N solution) was stirred
at room temperature for 96 hours. The solution was evaporated in
vacuo and purified by RP-HPLC to afford the title compound, [LCMS
(Method A, Mobile Phase II) RT=2.59 min, MH.sup.+ 282].
Preparation 3
(a) Ethyl
3-(1H-benzimidazol-1-yl)-3-(4-ethylphenyl)-2-propenoate
##STR00016##
To a solution of benzimidazole (118 mg, 1.00 mmol) in DMF (3 mL)
was added ethyl 3-(4-ethylphenyl)-2-propynoate (202 mg, 1.00 mmol)
and potassium carbonate (152 mg, 1.10 mmol). This suspension was
heated to 100.degree. C. for 48 hours, then cooled to room
temperature, and evaporated in vacuo. The residue was partitioned
between water and dichloromethane, and the separated aqueous layer
extracted with dichloromethane. The combined organic layers were
dried over anhydrous magnesium sulfate, filtered, and evaporated in
vacuo. The residue was purified by flash column chromatography on
silica gel, eluting with a mixture of dichloromethane and methanol
(96:4) to afford (in order of elution), ethyl
(2Z)-3-(1H-benzimidazol-1-yl)-3-(4-ethylphenyl)-2-propenoate, mixed
fractions, and ethyl
(2E)-3-(1H-benzimidazol-1-yl)-3-(4-ethylphenyl)-2-propenoate.
E isomer; .sup.1H NMR: (CDCl.sub.3), 8.02 (s, 1H), 7.90 (dd,
J=8.06, 0.73, 1H), 7.34-7.20 (m, 6H), 6.97 (d, J=8.06, 1H), 6.48
(s, 1H), 4.05 (q, J=6.96, 2H), 2.73 (q, J=7.69, 2H), 1.30 (t,
J=7.69, 3H), 1.05 (t, J=6.96, 3H)
Z isomer; .sup.1H NMR: (CDCl.sub.3), 7.87 (s, 1H), 7.83 (d, J=8.06,
1H), 7.34-7.22 (m, 6H), 7.15 (d, J=8.06, 1H), 6.27 (s, 1H), 4.16
(q, J=6.96, 2H), 2.74 (q, J=7.69, 2H), 1.30 (t, J=7.69, 3H), 1.21
(t, J=6.96, 3H).
(b) Example 3b
(2E)-3-(1H-Benzimidazol-1-yl)-3-(4-ethylphenyl)-2-propenoic
acid
##STR00017##
A solution of ethyl
(2E)-3-(1H-benzimidazol-1-yl)-3-(4-ethylphenyl)-2-propenoate (46
mg, 143 .mu.mol) in hydrochloric acid (10 mL of a 5N solution) was
stirred at room temperature for 72 hours, and then heated at reflux
for 6 hours. The solution was cooled to room temperature, and
evaporated in vacuo to afford the title compound, [LCMS (Method A,
Mobile Phase I) RT=6.62 min, MH.sup.+ 294].
(c) Example 3c
(2Z)-3-(1H-Benzimidazol-1-yl)-3-(4-ethylphenyl)-2-propenoic
acid
##STR00018##
A solution of ethyl
(2Z)-3-(1H-benzimidazol-1-yl)-3-(4-ethylphenyl)-2-propenoate (60
mg, 187 .mu.mol) in hydrochloric acid (10 mL of a 5N solution) was
stirred at room temperature for 72 hours, and then heated at reflux
for 6 hours. The solution was cooled to room temperature, and
evaporated in vacuo to afford the title compound, [LCMS (Method A,
Mobile Phase I) RT=6.63 min, MH.sup.+ 294].
Preparation 4
(a) Ethyl 3-(1H-benzimidazol-1-yl)-3-(4-ethylphenyl)propanoate
##STR00019##
To a solution of ethyl
3-(1H-benzimidazol-1-yl)-3-(4-ethylphenyl)-2-propenoate (E/Z
mixture, 181 mg, 566 .mu.mol) in a mixture of ethanol and water
(10:1, 2.75 mL) was added palladium on carbon (27 mg, 10% w/w Pd)
and ammonium formate (143 mg, 2.26 mmol). The suspension was
brought to reflux for 3 hours, cooled to room temperature, and was
filtered through a pad of Celite.RTM. and evaporated in vacuo. The
residue was purified by flash column chromatography on silica gel,
eluting with a mixture of dichloromethane and methanol (96:4) to
afford the title compound, .sup.1H NMR: (CDCl.sub.3), 8.03 (s, 1H),
(d, J=6.96, 1H), 7.31-7.06 (m, 7H), 6.01 (dd, J=8.79, 6.59, 1H),
4.04 (t, J=6.96, 2H), 3.38 (dd, J=15.75, 8.79, 1H), 3.31 (dd,
J=15.75, 6.59, 1H), 2.62 (q, J=7.69, 2H), 1.18 (t, J=7.69, 3H),
1.09 (t, J=6.96, 3H).
(b) Example 4b
3-(1H-Benzimidazol-1-yl)-3-(4-ethylphenyl)propanoic acid
##STR00020##
A suspension of ethyl
3-(1H-benzimidazol-1-yl)-3-(4-ethylphenyl)propanoate (180 mg, 559
.mu.mol) in hydrochloric acid (10 mL of a 5N solution) was stirred
at room temperature for 72 hours. A mixture of acetonitrile and
methanol (10:1, 11 mL) was added, and the resulting solution
stirred at room temperature for 110 hours. The solution was warmed
to reflux for 24 hours, and evaporated in vacuo. The residue was
taken up into aqueous sodium carbonate, and the resulting solution
extracted with diethyl ether. The aqueous phase was acidified with
dilute hydrochloric acid (pH<4), and extracted with
dichloromethane. The combined dichloromethane extracts were
evaporated in vacuo to afford the title compound, [LCMS (Method A,
Mobile Phase I) RT=4.20 min, MH.sup.+ 296].
Preparation 5
(a) Ethyl
3-(1H-benzimidazol-1-yl)-3-(1,1'-biphenyl)-4-yl-2-propenoate
##STR00021##
Using the process in Preparation 3, ethyl
3-(1,1'-biphenyl)-4-yl-2-propynoate gave the title compound (318
mg) as an approximate 3:1 mix of geometric isomers, as determined
by .sup.1H NMR. .sup.1H NMR: (CDCl.sub.3) of the mixture, 8.01 (s),
7.92-7.16 (m), 6.95 (d, J=8.06), 6.51 (s), 6.31 (s), 4.18 (q,
J=7.32), 4.01 (q, J=7.32), 1.22 (t, J=7.32), 1.00 (t, J=7.32).
(b) Ethyl
3-(1H-benzimidazol-1-yl)-3-(1,1'-biphenyl)-4-ylpropanoate
##STR00022##
To a solution of ethyl
3-(1H-benzimidazol-1-yl)-3-(1,1'-biphenyl)-4-yl-2-propenoate (318
mg, 861 .mu.mol) in a mixture of ethanol and water (17:2, 4.2 mL)
was added palladium on carbon (47 mg, 10% w/w Pd) and ammonium
formate (218 mg, 3.46 mmol). The suspension was brought to reflux
for 3 hours, cooled to room temperature, and was filtered through a
pad of Celite.RTM. and evaporated in vacuo. The residue was
purified by flash column chromatography on silica gel, eluting with
a mixture of dichloromethane and methanol (97:3) to afford the
title compound, [LCMS (Method A, Mobile Phase I) RT=6.51 min,
MH.sup.+ 371.7].
(c) Example 5c
3-(1H-Benzimidazol-1-yl)-3-(1,1'-biphenyl)-4-ylpropanoic acid
##STR00023##
A solution of ethyl
3-(1H-benzimidazol-1-yl)-3-(1,1'-biphenyl)-4-ylpropanoate (276 mg,
746 .mu.mol) in hydrochloric acid (50 mL of a 5N solution) was
stirred at room temperature for 12 hours. Acetonitrile (I mL) was
then added, and stirring continued for 110 hours. The solution was
warmed to reflux for 24 hours and was then cooled to room
temperature and evaporated in vacuo. The residue was taken up into
aqueous sodium carbonate and the resulting solution extracted with
diethyl ether. The aqueous phase was acidified with dilute
hydrochloric acid (pH<4), and re-extracted with dichloromethane.
The combined dichloromethane extracts were evaporated in vacuo, and
the residue was recrystallized from methanol to afford the title
compound, [LCMS (Method A, Mobile Phase I) RT=4.66 min, MH.sup.+
343].
Preparation 6
(a) Ethyl
3-[4-bromo-6-(trifluoromethyl)-1H-benzimidazol-1-yl]-3-phenyl-2--
propenoate
##STR00024##
To a solution of 4-bromo-6-trifluoromethylbenzimidazole (1.00 g,
3.77 mmol) in DMF (10 mL) was added potassium carbonate (520 mg,
3.77 mmol) and ethyl phenylpropiolate (690 .mu.L, 4.15 mmol). The
suspension was then warmed to 100.degree. C. for 4 hours, cooled to
room temperature, and was evaporated in vacuo. The residue was
purified by flash column chromatography on silica gel, eluting with
a mixture of dichloromethane and methanol (99:1), to afford the
title compound as a mixture of geometric isomers (ca. 6:1 as
determined by .sup.1H NMR). .sup.1H NMR: (CDCl.sub.3) of the
mixture, 8.16 (s), 8.13 (s), 7.76 (br), 7.57-7.17 (m), 6.61 (s),
6.30 (s), 4.18 (q, J=7.32), 4.07 (q, J=7.32), 1.21 (t, J=7.32),
1.10 (t, J=7.32).
(b) Ethyl
3-phenyl-3-[6-(trifluoromethyl)-1H-benzimidazol-1-yl]propanoate
##STR00025##
To a solution of ethyl
3-[4-bromo-6-(trifluoromethyl)-1H-benzimidazol-1-yl]-3-phenyl-2-propenoat-
e (111 mg, 253 .mu.mol) in ethanol (4 mL) was added palladium on
carbon (23 mg, 10% w/w Pd) and ammonium formate (159 mg, 2.52
mmol). The suspension was heated to reflux for 3 hours, then cooled
to room temperature, and filtered through a pad of Celite.RTM.. The
filtrate was evaporated in vacuo to afford the title compound,
.sup.1H NMR: (CDCl.sub.3), 8.10 (s, 1H), 7.79 (d, J=8.79, 1H), 7.49
(s, 1H), 7.42 (d, H=8.79, 1H), 7.31-7.23 (m, 3H), 7.18-7.14 (m,
2H), 6.00 (dd, J=6.96, 6.96, 1H), 3.98 (q, J=7.32, 2H), 3.36-3.25
(m, 2H), 1.03 (t, J=7.32, 3H).
(c) Example 6c
3-Phenyl-3-[6-(trifluoromethyl)-1H-benzimidazol-1-yl]propanoic
acid
##STR00026##
A solution of ethyl
3-phenyl-3-[6-(trifluoromethyl)-1H-benzimidazol-1-yl]propanoate (74
mg, 204 .mu.mol) in hydrochloric acid (10 mL of a 5N solution) was
stirred at room temperature for 96 hours. The solution was
evaporated in vacuo to afford the title compound, [LCMS (Method A,
Mobile Phase II) RT=4.07 min, MH.sup.+ 335].
Preparation 7
(a) tert-Butyl (3R)-3-(2-nitroanilino)-3-phenylpropanoate
##STR00027##
To a solution of 2-fluoronitrobenzene (150 mg, 1.06 mmol) in
dichloromethane (4 mL) was added tert-butyl
(3R)-3-amino-3-phenylpropanoate (235 mg, 1.06 mmol) and
triethylamine (300 .mu.L, 2.12 mmol). The solution was stirred at
room temperature for 4 hours, and was then evaporated in vacuo. The
residue was purified by flash column chromatography on silica gel,
eluting with dichloromethane, to afford the title compound, .sup.1H
NMR: (CD.sub.3OD), 8.76 (br m, 1H), 8.18 (d, J=7.69, 1H), 7.44 (d,
J=7.69, 2H), 7.40-7.37 (m, 2H), 7.32-7.28 (m, 1H), 6.84 (d, J=8.79
1H), 6.73-6.69 (m, 1H), 5.12 (dd, J=13.18, 6.59 1H), 2.91 (d,
J=6.59 2H), 1.41 (s, 9H).
(b) tert-Butyl (3R)-3-(2-aminoanilino)-3-phenylpropanoate
##STR00028##
To a solution of tert-butyl
(3R)-3-(2-nitroanilino)-3-phenylpropanoate (100 mg, 292 .mu.mol) in
a mixture of ethanol and water (4 mL, 3:1), was added palladium on
carbon (20 mg, 10% w/w Pd) and ammonium formate (191 mg, 3.03
mmol). The suspension was heated to reflux for 10 minutes, and was
then cooled to room temperature, filtered through a pad of
Celite.RTM., and evaporated in vacuo. The residue was purified by
flash column chromatography on silica gel, eluting with a mixture
of dichloromethane and methanol (98:2) to afford the title
compound, .sup.1H NMR: (CD.sub.3OD) 7.41 (d, J=7.3, 1H), 7.33-7.31
(m, 2H), 7.25-7.21 (m, 1H), 6.75-6.73 (m, 1H), 6.72-6.52 (m, 2H),
6.47-6.45 (m, 1H), 4.82 (obs., 1H), 2.87 (dd, J=14.6, 7.7, 1H),
2.74 (dd, J=14.6, 6.2, 1H), 1.41 (s, 9H).
(c) tert-Butyl (3R)-3-(1H-benzimidazol-1-yl)-3-phenylpropanoate
##STR00029##
To a solution of tert-butyl
(3R)-3-(2-aminoanilino)-3-phenylpropanoate (78 mg, 250 .mu.mol) in
2-ethoxyethanol (2 mL), was added formamidine acetate (41 mg, 394
.mu.mol). The solution was heated at 80.degree. C. for 1.75 hours,
and was then evaporated in vacuo. The residue was purified by flash
column chromatography on silica gel, eluting with a mixture of
dichloromethane and methanol (98:2) to afford the title compound,
[LCMS (Method A, Mobile Phase I) RT=6.30 min, MH.sup.+ 323].
(d) Example 7d
(3R)-3-(1H-Benzimidazol-1-yl)-3-phenylpropanoic acid
##STR00030##
A solution of tert-butyl
(3R)-3-(1H-benzimidazol-1-yl)-3-phenylpropanoate (92 mg, 285
.mu.mol) in hydrochloric acid (20 mL of a 5N solution) was stirred
at room temperature for 48 hours. The solution was then evaporated
in vacuo to give a gum. Trituration of this residue with diethyl
ether afforded the title compound, [LCMS (Method B, Mobile Phase I)
RT=3.45 min, MH.sup.+ 267].
The corresponding S-enantiomer was prepared with a similar
procedure, using tert-butyl (3S)-3-amino-3-phenylpropanoate, to
give the title compound, [LCMS (Method A, Mobile Phase I) RT=3.43
min, MH.sup.+ 267].
A racemic mixture was prepared using the procedure as described in
Preparation 2. Benzimidazole and ethyl phenylpropiolate gave the
title compound, [LCMS (Method A, Mobile Phase II) RT=3.35 min,
MH.sup.+ 267].
Example 8
3-(1H-Benzimidazol-1-yl)-3-(4-chlorophenyl)propanoic acid
##STR00031##
Using the procedure of Preparation 7, the title compound, (12.7
mg), was prepared using ethyl 3-amino-3-(4-chlorophenyl)propanoate
as a starting material [prepared from commercially available
(4-chlorophenyl)-.beta.-alanine according to literature methods].
[LCMS (Method A, Mobile Phase I) RT=4.01 min, MH.sup.+ 301].
Example 9
(3R)-3-(1H-Benzimidazol-1-yl)-4-phenylbutanoic acid
##STR00032##
Using the procedure of Preparation 7, tert-butyl
(3R)-3-amino-4-phenylbutanoate gave the title compound (91 mg),
[LCMS (Method A, Mobile Phase I) RT=3.62 min, MH.sup.+ 282].
Starting from tert-butyl (3S)-3-amino-4-phenylbutanoate, the
corresponding S-enantiomer, (204 mg), was prepared in a similar
manner. [LCMS (Method A, Mobile Phase I) RT=3.54 min, MH=282].
Preparation 10
(a) 3-{3-[(4-Methoxybenzyl)amino]-2-nitroanilino}-3-phenylpropanoic
acid
##STR00033##
To a solution of 2,6-difluoronitrobenzene (200 mg, 1.26 mmol) in
DMSO (2 mL) was added 3-amino-3-phenylpropionic acid (228 mg, 1.39
mmol) and potassium carbonate (347 mg, 2.52 mmol). The suspension
was heated to 100.degree. C. for 0.5 hour, and 4-methoxybenzylamine
(180 .mu.L, 1.39 mmol) was added, and heating continued for a
further 3 hours. The suspension was cooled to room temperature, and
partitioned between water and ethyl acetate. The aqueous layer was
acidified with dilute hydrochloric acid (pH<4), and then
extracted with ethyl acetate. The combined ethyl acetate extracts
were dried over anhydrous magnesium sulfate, filtered, and
evaporated in vacuo. The residue was purified by flash column
chromatography on silica gel, eluting with a mixture of
dichloromethane and methanol (19:1) to afford the title compound,
[LCMS (Method A, Mobile Phase II) RT=4.75 min, MH.sup.+ 422].
(b) 3-{2-Amino-3-[(4-methoxybenzyl)amino]anilino}-3-phenylpropanoic
acid
##STR00034##
To a solution of
3-{3-[(4-methoxybenzyl)amino]-2-nitroanilino}-3-phenylpropanoic
acid (176 mg, 418 .mu.mol) in ethanol (6 mL) was added Raney-nickel
(Aldrich22, 167-8, catalytic, ca. 5 mg) and hydrazine hydrate (200
.mu.L, 4.12 mmol). The resulting suspension was stirred at room
temperature for 0.6 hour. The suspension was filtered through
Celite.RTM., and the pad washed with ethanol. The combined
filtrates were evaporated in vacuo, and the residue purified by
flash column chromatography on silica gel, eluting with a mixture
of dichloromethane and methanol (19:1) to afford the title
compound, .sup.1H NMR: (CD.sub.3OD), 7.76-7.74 (m, 1H), 7.66-7.61
(m, 1H), 7.41-7.20 (m, 7H), 6.91-6.87 (m, 2H), 6.50-6.46 (m, 1H),
6.23-6.21 (m, 1H), 6.07-6.05 (m, 1H), 4.81 (br t, J=6.59, 1H),
4.27-4.24 (m, 3H), 3.80 (s, 3H), 2.90 (dd, J=15.38, 8.79, 1H), 2.76
(dd, J=15.38, 9.89, 1H).
(c) Example 10c
N-[1-(4-Methoxybenzyl)-1H-benzimidazol-4-yl]-3-phenylpropanoic
acid
##STR00035##
A solution of
3-{2-amino-3-[(4-methoxybenzyl)amino]anilino}-3-phenylpropanoic
acid (18 mg, 46 .mu.mol) in triethylorthoformate (2 mL) was heated
at 100.degree. C. for 2 hours. The solution was then cooled to room
temperature, evaporated in vacuo, and the residue purified by
RP-HPLC to afford the title compound, [LCMS (Method A, Mobile Phase
II) RT=4.36 min, MH.sup.+ 402].
Preparation 11
(a) 3-[3-(Benzylamine)-2-nitroanilino]-3-phenylpropanoic acid
##STR00036##
To a solution of 2,6-difluoronitrobenzene (500 mg, 3.14 mmol) in
DMSO (3 mL) was added 3-amino-3-phenylpropionic acid (623 mg, 3.77
mmol) and potassium carbonate (529 mg, 3.83 mmol). The suspension
was heated to 100.degree. C. for 0.5 hour, then benzylamine (410
.mu.L, 3.75 mmol) was added, and heating continued for a further 3
hours. The suspension was cooled to room temperature, and
partitioned between water and ethyl acetate. The aqueous layer was
separated and acidified with dilute hydrochloric acid (pH<4),
and extracted with ethyl acetate. The combined ethyl acetate
extracts were dried over anhydrous magnesium sulfate, filtered, and
evaporated in vacuo. The residue was purified by flash column
chromatography on silica gel, eluting with a mixture of
dichloromethane and methanol (97:3) to afford the title compound,
.sup.1H NMR: (CD.sub.3OD) 7.45-7.21 (m, 10H), 6.98 (dd, J=8.42,
8.42, 1H), 5.97 (d, J=8.42, 1H), 5.87 (d, J=8.79, 1H), 5.07-5.01
(m, 1H), 4.40-4.43 (m, 2H), 2.95-2.81 (m, 2H).
(b) 3-[2-Amino-3-(benzylamine)anilino]-3-phenylpropanoic acid
##STR00037##
To a solution of
3-[3-(benzylamine)-2-nitroanilino]-3-phenylpropanoic acid (75 mg,
192 .mu.mol) in a mixture of 1,4-dioxane, water and 0.88 ammonia
solution (3:3:0.1, 6.1 mL) was added sodium dithionite (267 mg,
1.53 mmol). The solution was stirred at room temperature for 0.1
hour, and then extracted with ethyl acetate. The combined ethyl
acetate extracts were dried over anhydrous magnesium sulfate,
filtered, and evaporated in vacuo to afford the title compound,
[LCMS (Method A, Mobile Phase II) RT=4.35 min, MH.sup.+ 362].
(c) Example 11c
N-(1-Benzyl-1H-benzimidazol-4-yl)-3-phenylpropanoic acid
##STR00038##
A solution of 3-[2-amino-3-(benzylamine)anilino]-3-phenylpropanoic
acid (35 mg, 97 .mu.mol) in triethylorthoformate (2 mL) was heated
to 100.degree. C. for 0.6 hour. The solution was evaporated in
vacuo, and the residue dissolved in a mixture of hydrochloric acid
(10 mL of a 5N solution) and acetonitrile (5 mL). This solution was
stirred at room temperature for 48 hours, and then evaporated in
vacuo. The residue was purified by RP-HPLC to afford the title
compound, [LCMS (Method A, Mobile Phase II) RT=4.31 min, MH.sup.+
372.5].
Preparation 12
(a)
1-{3-[(3-Methoxy-3-oxo-1-phenylpropyl)amino]-2-nitrophenyl}-4-piperidi-
necarboxylic acid
##STR00039##
To a solution of 2,6-difluoronitrobenzene (272 mg, 1.71 mmol) in
DMSO (2 mL) was added methyl-3-amino-3-phenylpropanoate (553 mg,
2.57 mmol) and potassium carbonate (709 mg, 5.13 mmol), and the
suspension stirred at room temperature for 24 hours.
4-Piperidinecarboxylic acid (335 mg, 2.59 mmol) was added, and the
resulting suspension stirred at room temperature for 24 hours, and
then heated at 100.degree. C. for 3 hours. The suspension was
cooled to room temperature, and diluted with water. The aqueous
solution was extracted with ethyl acetate, and the separated
aqueous layer acidified with dilute hydrochloric acid (pH<4),
and re-extracted with ethyl acetate. The second organic extracts
were evaporated in vacuo, and the residue purified by flash column
chromatography on silica gel, eluting with a mixture of
dichloromethane and methanol (96:4) to afford the title compound,
.sup.1H NMR: (CDCl.sub.3) 7.36-7.22 (m, 5H), 7.02 (t, J=8.06, 1H),
6.34 (dd, J=8.06, 1.10, 1H), 6.19 (d, J=8.06, 1H), 4.89-4.85 (m,
1H), 3.66 (s, 3H), 3.25-3.21 (m, 2H), 2.87-2.77 (m, 4H), 2.48-2.41
(m, 1H), 2.02-1.82 (m, 4H).
(b)
1-[1-(3-Methoxy-3-oxo-1-phenylpropyl)-1H-benzimidazol-4-yl]-4-piperidi-
necarboxylic acid
##STR00040##
To a solution of
1-{3-[(3-methoxy-3-oxo-1-phenylpropyl)amino]-2-nitrophenyl}-4-piperidinec-
arboxylic acid (696 mg, 1.63 mmol) in ethanol (5 mL) was added
Raney-Nickel (catalytic, ca. 5 mg) and hydrazine hydrate (316
.mu.L, 6.52 mmol). The solution was stirred at room temperature for
3 hours, filtered, and evaporated in vacuo. The residue (560 mg)
was dissolved in triethylorthoformate (5 mL), and heated at
60.degree. C. for 0.5 hour. The resulting solution was cooled to
room temperature, and evaporated in vacuo. The residue was purified
by flash column chromatography on silica gel, eluting with a
mixture of dichloromethane and methanol (92:8) to afford the title
compound, .sup.1H NMR: (CD.sub.3OD) 8.27 (s, 1H), 7.34-7.28 (m,
5H), 7.10 (t, J=8.06, 1H), 6.99 (br d, J=8.06, 1H), 6.68 (d,
J=8.06, 1H), 6.08 (dd, J=9.16, 6.22, 1H), 3.95-3.91 (m, 2H), 3.59
(obs dd, J=16.11, 9.16, 1H), 3.59 (s, 3H), 3.45 (dd, J=16.11, 6.22,
1H), 2.86-2.80 (m, 2H), 2.47-2.43 (m, 1H), 2.06-1.98 (m, 4H).
(c) Methyl
3-phenyl-3-(4-{4-[(1,4,5,6-tetrahydro-2-pyrimidinylamino)carbon-
yl]-1-piperidinyl}-1H-benzimidazol-1-yl)propanoate
##STR00041##
To a solution of
1-[1-(3-methoxy-3-oxo-1-phenylpropyl)-1H-benzimidazol-4-yl]-4-piperidinec-
arboxylic acid (70 mg, 172 .mu.mol) in DMF was added
N,N-diisopropylethylamine (60 .mu.L, 344 .mu.mol) and TBTU (66 mg,
206 .mu.mol). The solution was stirred at room temperature for 0.5
hour, then 2-amino-1,4,5,6-tetrahydropyrimidine hydrobromide (34
mg, 189 .mu.mol) was added. The mixture was heated to 80.degree. C.
for 8 hours, cooled to room temperature, and evaporated in vacuo.
The residue was purified by RP-HPLC to afford the title compound,
[LCMS (Method A, Mobile Phase II) RT=4.66 min, MH.sup.+ 489].
(d) Example 12d
3-Phenyl-3-(4-{4-[(1,4,5,6-tetrahydro-2-pyrimidinylamino)carbonyl]-1-piper-
idinyl}-1H-benzimidazol-1-yl)propanoic acid
##STR00042##
A solution of methyl
3-phenyl-3-(4-{4-[(1,4,5,6-tetrahydro-2-pyrimidinylamino)carbonyl]-1-pipe-
ridinyl}-1H-benzimidazol-1-yl)propanoate (17 mg, 24 .mu.mol) in
hydrochloric acid (10 mL of a 5N solution) was stirred at room
temperature for 48 hours. The solution was evaporated in vacuo, and
the residue purified by RP-HPLC to afford the title compound, [LCMS
(Method A, Mobile Phase II) RT=3.5 min, MH.sup.+ 475].
Preparation 13
(a) Ethyl
3-{5-[(4-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropa-
noate
##STR00043##
To a solution of ethyl
3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (100 mg, 324
.mu.mol) in dichloromethane (6 mL) was added triethylamine (100
.mu.L, 710 .mu.mol) and 4-nitrobenzoyl chloride (132 mg, 712
.mu.mol). The solution was stirred at room temperature for 96
hours, and was evaporated in vacuo. The residue was purified by
flash column chromatography on silica gel, eluting with
dichloromethane and methanol (97:3) to afford the title compound,
[LCMS (Method A, Mobile Phase I) RT=4.92 min, MH.sup.+ 459].
(b) Example 13b
3-{5-[(4-Nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
##STR00044##
A solution of ethyl
3-{5-[(4-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate
(60 mg, 131 .mu.mol) in a mixture of acetonitrile (10 mL) and
hydrochloric acid (20 mL of a 5N solution) was stirred at room
temperature for 72 hours. The resulting precipitate was collected
by filtration, and air-dried to afford the title compound, [LCMS
(Method A, Mobile Phase II) RT=3.84 min, MH.sup.+ 431].
Preparation 14
(a) Ethyl
3-{5-[(4-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropa-
noate
##STR00045##
To a solution of ethyl
3-{5-[(4-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate
(297 mg, 648 .mu.mol) in a mixture of ethanol and water (4:1, 10
mL), was added palladium on carbon (60 mg, 10% w/w Pd) and ammonium
formate (245 mg, 3.89 mmol). The resulting suspension was heated to
reflux for 2 hours, and was then cooled to room temperature, and
filtered through a pad of Celite.RTM.. The filtrate was evaporated
to dryness, to afford the crude title compound, which was used
directly without further purification, [LCMS (Method A, Mobile
Phase I) RT=4.04 min, MH.sup.+ 430].
(b) Example 14b
3-{5-[(4-Aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
##STR00046##
A solution of ethyl
3-{5-[(4-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate
(50 mg, 117 .mu.mol) was dissolved in hydrochloric acid (25 mL of a
5N solution), and stirred at room temperature for 110 hours. The
solution was evaporated in vacuo to afford the title compound,
[LCMS (Method A, Mobile Phase II) RT=3.27 min, MH.sup.+ 401].
Preparation 15
(a) Ethyl
3-{5-[(4-{[amino(imino)methyl]amino}benzoyl)amino]-1H-benzimidaz-
ol-1-yl}-3-phenylpropanoate
##STR00047##
To a solution of ethyl
3-{5-[(4-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate
(60 mg, 140 .mu.mol) in acetonitrile (1.2 mL) was added
benzotriazolo-1-carboxamidine tosylate (55 mg, 157 .mu.mol). The
resulting suspension was heated to reflux for 16 h, then cooled to
room temperature, evaporated in vacuo, and the residue purified by
RP-HPLC to afford the title compound, [LCMS (Method A, Mobile Phase
II) RT=4.25 min, MH.sup.+ 471].
(b) Example 15b
3-{5-[(4-{[Amino(imino)methyl]amino}benzoyl)amino]-1H-benzimidazol-1-yl}-3-
-phenylpropanoic acid
##STR00048##
A solution of ethyl
3-{5-[(4-{[amino(imino)methyl]amino}benzoyl)amino]-1H-benzimidazol-1-yl}--
3-phenylpropanoate (4.0 mg, 8.5 .mu.mol) in hydrochloric acid (10
mL of a 5N solution) was stirred at room temperature for 72 hours.
The solution was then evaporated in vacuo to afford the title
compound, [LCMS (Method A, Mobile Phase II) RT=2.95 min, MH.sup.+
443].
Preparation 16
(a) Ethyl
3-{5-[(3-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropa-
noate
##STR00049##
To a solution of ethyl
3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (250 mg, 809
.mu.mol) in dichloromethane (15 mL) was added triethylamine (280
.mu.L, 2.03 mmol), 3-nitrobenzoyl chloride (375 mg, 2.03 mmol) and
DMAP (10 mg, 81 .mu.mol). The solution was stirred at room
temperature for 144 hours, and was then evaporated in vacuo. The
residue was purified by flash column chromatography on silica gel,
eluting with a mixture of dichloromethane and methanol (97:3) to
afford the title compound, [LCMS (Method A, Mobile Phase II)
RT=5.53 min, MH.sup.+ 459].
(b) Example 16b
3-{5-[(3-Nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
##STR00050##
A solution of ethyl
3-{5-[(3-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate
(40 mg, 87 .mu.mol) in hydrochloric acid (20 mL of a 5N solution)
was stirred at room temperature for 110 hours. The solution was
then evaporated in vacuo, and purified by RP-HPLC to give the title
compound, [LCMS (Method A, Mobile Phase II) RT=3.91 min, MH.sup.+
431].
Preparation 17
(a) Ethyl
3-{5-[(3-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropa-
noate
##STR00051##
To a solution of ethyl
3-{5-[(3-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate
(190 mg, 415 .mu.mol) in a mixture of ethanol and water (4:1, 10
mL) was added palladium on carbon (38 mg, 10% w/w Pd) and ammonium
formate (130 mg, 2.06 mmol). The suspension was heated to reflux
for 2 hours, cooled to room temperature and filtered through a pad
of Celite.RTM.. The filtrate was then evaporated in vacuo to afford
the title compound, [LCMS (Method A, Mobile Phase I) RT=3.85 min,
MH.sup.+ 429].
(b) Example 17b
3-{5-[(3-Aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
##STR00052##
A solution of ethyl
3-{5-[(3-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate
(50 mg, 117 .mu.mol) in hydrochloric acid (20 mL of a 5N solution)
was stirred at room temperature for 110 hours. The solution was
then evaporated in vacuo, and the residue was purified by RP-HPLC
to afford the title compound, [LCMS (Method A, Mobile Phase II)
RT=3.25 min, MH.sup.+ 401].
Preparation 18
(a) Ethyl
3-{5-[(3-{[amino(imino)methyl]amino}benzoyl)amino]-1H-benzimidaz-
ol-1-yl}-3-phenylpropanoate
##STR00053##
To a solution of ethyl
3-{5-[(3-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate
(60 mg, 140 .mu.mol) in acetonitrile (1.2 mL) was added
benzotriazolo-1-carboxamidine tosylate (50 mg, 142 .mu.mol). The
resulting suspension was heated to reflux for 16 hours, cooled to
room temperature, and evaporated in vacuo. The residue was purified
by RP-HPLC to afford the title compound, [LCMS (Method A, Mobile
Phase II) RT=4.19 min, MH.sup.+ 471].
(b) Example 18b
3-{5-[(3-{[Amino(imino)methyl]amino}benzoyl)amino]-1H-benzimidazol-1-yl}-3-
-phenylpropanoic acid
##STR00054##
A solution of ethyl
3-{5-[(3-{[amino(imino)methyl]amino}benzoyl)amino]-1H-benzimidazol-1-yl}--
3-phenylpropanoate (32 mg, 68 .mu.mol) in hydrochloric acid (20 mL
of a 5N solution) was stirred at room temperature for 96 hours. The
solution was evaporated in vacuo and the residue was purified by
RP-HPLC to afford the title compound, [LCMS (Method A, Mobile Phase
II) RT=2.99 min, MH.sup.+ 443].
Preparation 19
(a) Ethyl
3-{5-[(2-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropa-
noate
##STR00055##
To a solution of ethyl
3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (250 mg, 809
.mu.mol) in dichloromethane (15 mL) was added triethylamine (250
.mu.L, 1.78 mmol) and 2-nitrobenzoyl chloride (240 .mu.L, 1.78
mmol). The solution was stirred at room temperature for 110 hours,
and was then evaporated in vacuo. The residue was purified by flash
column chromatography on silica gel, eluting with a mixture of
dichloromethane and methanol (97:3) to afford the title compound,
[LCMS (Method A, Mobile Phase II) RT=5.23 min, MH.sup.+ 459].
(b) Ethyl
3-{5-[(2-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropa-
noate
##STR00056##
To a solution of ethyl
3-{5-[(2-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate
(30 mg, 66 .mu.mol) in a mixture of ethanol and water (4:1, 5 mL),
was added palladium on carbon (6.0 mg, 10% w/w Pd) and ammonium
formate (20 mg, 317 .mu.mol). The suspension was heated to reflux
for 3 hours, then cooled to room temperature, and filtered through
a pad of Celite.RTM.. The filtrate was evaporated in vacuo to
afford the title compound, .sup.1H NMR: (CD.sub.3OD), 8.48 (s, 1H),
8.06 (s, 1H), 7.64 (dd, J=7.69, 1.46, 1H), 7.50-7.35 (br, 7H),
7.28-7.24 (m, 1H), 6.82 (dd, J=8.42, 0.73 1H), 6.74-6.70 (m, 1H),
6.18 (dd, J=9.52, 5.86, 1H), 4.09 (1, J=7.32, 2H), 3.66 (dd,
J=16.11, 9.52, 1H), 3.51 (dd, J=16.11, 5.86, 1H), 1.13 (t, J=7.32,
3H).
(c) Example 19c
3-{5-[(2-Aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
##STR00057##
A solution of ethyl
3-{5-[(2-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate
(15 mg, 35 .mu.mol) in hydrochloric acid (10 mL of a 5N solution)
was stirred at room temperature for 72 hours. The solution was then
evaporated in vacuo, and the residue was purified by RP-HPLC to
afford the title compound, [LCMS (Method A, Mobile Phase II)
RT=3.75 min, MH.sup.+ 401].
Preparation 20
(a) Ethyl
3-{5-[(anilinocarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylprop-
anoate
##STR00058##
To a solution of ethyl 3-(5-amino-1H-benzimidazol-1-yl)-3-phenyl
propanoate (0.400 g, 1.29 mmol) in methanol (15 mL) was added
phenyl isocyanate (170 .mu.L, 1.56 mmol) and
N,N-diisopropylethylamine (270 .mu.L, 1.55 mmol). The solution was
stirred at room temperature for 72 hours, and then evaporated in
vacuo. The residue was purified by flash column chromatography on
silica gel, eluting with a mixture of dichloromethane and methanol
(95:5) to afford the title compound, [LCMS (Method A, Mobile Phase
I) RT=4.68 min, MH.sup.+ 429], and the corresponding methyl ester
[LCMS (Method A, Mobile Phase I) RT=4.48 min, MH.sup.+ 415] in a
2:1 ratio.
(b) Example 20b
3-{5-[(Anilinocarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
##STR00059##
A solution of ethyl
3-{5-[(anilinocarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate
(491 mg, 1.14 mmol) in a mixture of hydrochloric acid (40 mL of a
5N solution) and acetonitrile (20 mL) was stirred at room
temperature for 24 hours. Additional aliquotes of hydrochloric acid
(20 mL of a 5N solution) and acetonitrile (10 mL) were then added,
and stirring was continued for a further 72 hours. The solution was
then evaporated in vacuo to afford the title compound, [LCMS
(Method A, Mobile Phase I) RT=4.11 min, MH.sup.+ 401].
Preparation 21
(a) Ethyl
3-{5-[(2-phenoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpro-
panoate
##STR00060##
To a solution of 2-phenoxybenzoic acid (38 mg, 177 .mu.mol) in
acetonitrile (5 mL) was added N,N-diisopropylethylamine (40 .mu.L,
229 .mu.mol) and TBTU (62 mg, 193 .mu.mol). The solution was
stirred at room temperature for 0.5 hours, ethyl
3-(5-amino-1H-benzimidazol-1-yl)-3-phenyl propanoate (50 mg, 162
.mu.mol) was added, and stirring continued at room temperature for
24 hours. The solution was evaporated in vacuo, and the residue was
purified by flash column chromatography on silica gel, eluting with
a mixture of dichloromethane and methanol (95:5) to afford the
title compound. [LCMS (Method A, Mobile Phase I) RT=5.33 min,
MH.sup.+ 506].
(b) Example 21b
3-{5-[(2-Phenoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
##STR00061##
A solution of ethyl
3-{5-[(2-phenoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate
(68 mg, 135 .mu.mol) in a mixture of hydrochloric acid (20 mL of a
5N solution) and acetonitrile (20 mL) was stirred at room
temperature for 48 hours. The solution was then concentrated in
vacuo, and the resulting solid filtered off and vacuum-dried to
afford the title compound, [LCMS (Method A, Mobile Phase I) RT=2.70
min, MH.sup.+ 478].
Example 22
3-{5-[(2,6-Dimethoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
##STR00062##
Using the procedure of Preparation 21, the title compound (31 mg)
was prepared from ethyl
3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate and
2,6-dimethoxybenzoic acid. [LCMS (Method C, Mobile Phase I) RT=2.25
min, MH.sup.+ 446].
Example 23
3-Phenyl-3-[5-({[2-(phenylsulfanyl)-3-pyridinyl]carbonyl}amino)-1H-benzimi-
dazol-1-yl]propanoic acid
##STR00063##
Using the procedure of Preparation 21, the title compound (48 mg)
was prepared from ethyl 3-(5-amino-1H-benzimidazol-1-yl)-3-phenyl
propanoate and 2-(phenylsulfanyl)nicotinic acid, and purified by
RP-HPLC. [LCMS (Method A, Mobile Phase I) RT=4.35 min, MH.sup.+
495].
Example 24
3-(5-{[(2-Phenoxy-3-pyridinyl)carbonyl]amino}-1H-benzimidazol-1-yl)-3-phen-
ylpropanoic acid
##STR00064##
Using the procedure of Preparation 21, the title compound (52 mg)
was prepared from ethyl 3-(5-amino-1H-benzimidazol-1-yl)-3-phenyl
propanoate and 2-phenoxynicotinic acid, and purified by RP-HPLC.
[LCMS (Method A, Mobile Phase I) RT=4.51 min, MH.sup.+ 479].
Example 25
3-{5-[(2-Hydroxy-5-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropa-
noic acid
##STR00065##
Using a similar procedure to that described in Preparation 21, the
title compound (9 mg) was prepared from ethyl
3-(5-amino-1H-benzimidazol-1-yl)-3-phenyl propanoate and
2-hydroxy-5-nitrobenzoic acid (HATU was substituted for TBTU), and
purified by RP-HPLC. [LCMS (Method A, Mobile Phase I) RT=4.46 min,
MH.sup.+ 447].
Preparation 26
(a) Ethyl
3-{6-[(4-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropa-
noate
##STR00066##
To a solution of ethyl
3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (200 mg, 647
.mu.mol) in dichloromethane (15 mL) was added triethylamine (190
.mu.L, 1.43 mmol) and 4-nitrobenzoyl chloride (264 mg, 1.43 mmol).
The solution was stirred at room temperature for 72 hours, and was
then evaporated in vacuo. The residue was purified by flash column
chromatography on silica gel, eluting with a mixture of
dichloromethane and methanol (97:3) to afford the title compound,
[LCMS (Method A, Mobile Phase II) RT=5.42 min, MH.sup.+ 459].
(b) Example 26b
3-{6-[(4-Nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
##STR00067##
A solution of ethyl
3-{6-[(4-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate
(40 mg, 87 .mu.mol) in hydrochloric acid (20 mL of a 5N solution)
was stirred at room temperature for 110 hours. The solution was
then evaporated in vacuo, and the residue was purified by RP-HPLC
to afford the title compound, [LCMS (Method A, Mobile Phase II)
RT=3.89 min, MH.sup.+ 431].
Preparation 27
(a) Ethyl
3-{6-[(4-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropa-
noate
##STR00068##
To a solution of ethyl
3-{6-[(4-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate
(241 mg, 526 .mu.mol) in a mixture of ethanol and water (6:1, 14
mL) was added palladium on carbon (48 mg, 10% w/w Pd) and ammonium
formate (200 mg, 3.18 mmol). The suspension was heated to reflux
for 2 hours, and was then cooled to room temperature, and filtered
through a pad of Celite.RTM.. The filtrate was evaporated in vacuo
to afford the title compound, [LCMS (Method A, Mobile Phase II)
RT=4.61 min, MH.sup.+ 429].
(b) Example 27b
3-{6-[(4-Amino
benzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic acid
##STR00069##
A solution of ethyl
3-{6-[(4-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate
(50 mg, 117 .mu.mol) in hydrochloric acid (20 mL of a 5N solution)
was stirred at room temperature for 72 hours. The solution was then
evaporated in vacuo, and the residue was purified by RP-HPLC to
afford the title compound, [LCMS (Method A, Mobile Phase II)
RT=3.20 min, MH.sup.+ 401].
Preparation 28
(a) Ethyl
3-{6-[(4-{[amino(imino)methyl]amino}benzoyl)amino]-1H-benzimidaz-
ol-1-yl}-3-phenylpropanoate
##STR00070##
To a solution of ethyl
3-{6-[(4-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate
(60 mg, 140 .mu.mol) in acetonitrile (1.2 mL) was added
benzotriazolo-1-carboxamidine tosylate (50 mg, 142 .mu.mol). The
resulting suspension was then heated to reflux for 16 hours.
Additional benzotriazolo-1-carboxamidine tosylate (50 mg, 142
.mu.mol) was then added, and heating was continued for a further 16
hours. The suspension was cooled to room temperature, evaporated in
vacuo, and the residue was purified by RP-HPLC to afford the title
compound, [LCMS (Method A, Mobile Phase II) RT=3.86 min, MH.sup.+
471].
(b) Example 28b
3-{6-[(4-{[Amino(imino)methyl]amino}benzoyl)amino]-1H-benzimidazol-1-yl}-3-
-phenylpropanoic acid
##STR00071##
A solution of ethyl
3-{6-[(4-{[amino(imino)methyl]amino}benzoyl)amino]-1H-benzimidazol-1-yl}--
3-phenylpropanoate (15 mg, 32 .mu.mol) in hydrochloric acid (20 mL
of a 5N solution) was stirred at room temperature for 96 hours. The
solution was then evaporated in vacuo, and the residue was purified
by RP-HPLC to afford the title compound, [LCMS (Method A, Mobile
Phase II) RT=2.86 min, MH.sup.+ 443].
Preparation 29
(a) Ethyl
3-{6-[(3-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropa-
noate
##STR00072##
To a solution of ethyl
3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (200 mg, 647
.mu.mol) in dichloromethane (15 mL) was added triethylamine (190
.mu.L, 1.43 mmol) and 3-nitrobenzoyl chloride (264 mg, 1.43 mmol).
The solution was stirred at room temperature for 96 hours, and DMAP
(7.0 mg, 57 .mu.mol) and 3-nitrobenzoyl chloride (120 mg, 647
.mu.mol) was added, and the stirring continued at room temperature
for 72 hours. Triethylamine (90 .mu.L, 639 .mu.mol), 3-nitrobenzoyl
chloride (120 mg, 647 .mu.mol) and DMAP (7.0 mg, 57 .mu.mol) were
then added. The solution was stirred at room temperature for 72
hours, evaporated in vacuo, and the residue purified by flash
column chromatography on silica gel, eluting with a mixture of
dichloromethane and methanol (97:3), to afford the title compound,
[LCMS (Method A, Mobile Phase I) RT=5.52 min, MH.sup.+ 459].
(b) Example 29b
3-{6-[(3-Nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
##STR00073##
A solution of ethyl
3-{6-[(3-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate
(40 mg, 87 .mu.mol) in hydrochloric acid (20 mL of a 5N solution)
was stirred at room temperature for 96 hours. The solution was then
evaporated in vacuo, and the residue was purified by RP-HPLC to
afford the title compound, [LCMS (Method A, Mobile Phase II)
RT=3.92 min, MH.sup.+ 431].
Preparation 30
(a) Ethyl
3-{6-[(3-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropa-
noate
##STR00074##
To a solution of ethyl
3-{6-[(3-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate
(231 mg, 504 .mu.mol) in a mixture of ethanol and water (4:1, 10
mL), was added palladium on carbon (46 mg, 10% w/w Pd) and ammonium
formate (191 mg, 3.03 mmol). The suspension was heated to reflux
for 3 hours, and was then cooled to room temperature, and filtered
through a pad of Celite.RTM.. The filtrate was evaporated in vacuo
to afford the title compound, .sup.1H NMR: (CD.sub.3OD), 8.43 (s,
1H), 8.14 (d, J=1.46, 1H), 7.65 (d, J=8.79, 1H), 7.47 (dd, J=8.79,
1.83, 1H), 7.30 (br, 8H), 6.92-6.90 (m, 1H), 6.11 (dd, J=9.52,
6.22, 1H), 4.04 (q, J=7.32, 2H), 3.62 (dd, J=16.11, 9.52, 1H), 3.46
(dd, J=16.11, 6.22, 1H), 1.08 (t, J=7.32, 3H).
(b) Example 30b
3-{6-[(3-Aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
##STR00075##
A solution of ethyl
3-{6-[(3-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate
(50 mg, 117 .mu.mol) in hydrochloric acid (20 mL of a 5N solution)
was stirred at room temperature for 96 hours. The solution was
evaporated in vacuo, and the residue was purified by RP-HPLC to
afford the title compound, [LCMS (Method A, Mobile Phase II)
RT=3.36 min, MH.sup.+ 401].
Preparation 31
(a) Ethyl
3-{6-[(3-{[amino(imino)methyl]amino}benzoyl)amino]-1H-benzimidaz-
ol-1-yl}-3-phenylpropanoate
##STR00076##
To a solution of ethyl
3-{6-[(3-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate
(70 mg, 164 .mu.mol) in acetonitrile (1.2 mL) was added
benzotriazolo-1-carboxamidine tosylate (57 mg, 163 .mu.mol), and
the resulting suspension heated to reflux for 16 hours. The
suspension was then cooled to room temperature, evaporated in
vacuo, and the residue was purified by RP-HPLC to afford the title
compound, [LCMS (Method A, Mobile Phase II) RT=3.96 min, MH.sup.+
471].
(b) Example 31b
3-{6-[(3-{[Amino(imino)methyl]amino}benzoyl)amino]-1H-benzimidazol-1-yl}-3-
-phenylpropanoic acid
##STR00077##
A solution of ethyl
3-{6-[(3-{[amino(imino)methyl]amino}benzoyl)amino]-1H-benzimidazol-1-yl}--
3-phenylpropanoate (24 mg, 51 .mu.mol) in hydrochloric acid (20 mL
of a 5N solution) was stirred at room temperature for 72 hours. The
solution was evaporated in vacuo, and the residue was purified by
RP-HPLC to afford the title compound, [LCMS (Method A, Mobile Phase
II) RT=2.96 min, MH.sup.+ 443].
Preparation 32
(a) Ethyl
3-{6-[(2-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropa-
noate
##STR00078##
To a solution of ethyl
3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (200 mg, 647
.mu.mol) in dichloromethane (15 mL) was added triethylamine (200
.mu.L, 1.43 .mu.mol) and 2-nitrobenzoyl chloride (190 .mu.L, 1.43
mmol). The solution was stirred at room temperature for 96 hours,
and was evaporated in vacuo. The residue was purified by flash
column chromatography on silica gel, eluting with a mixture of
dichloromethane and methanol (97:3) to afford the title compound,
[LCMS (Method A, Mobile Phase II) RT=5.12 min, MH.sup.+ 459].
(b) Example 32b
3-{6-[(2-Nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid & Example 32c:
3-{6-[(2-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
##STR00079##
To a solution of ethyl
3-{6-[(2-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate
(24 mg, 52 .mu.mol) in a mixture of ethanol and water (5:1, 6 mL),
was added palladium on carbon (50 mg, 10% w/w Pd) and ammonium
formate (17 mg, 270 .mu.mol). The suspension was heated to reflux
for 2 hours, cooled to room temperature, filtered through a pad of
Celite.RTM. and the filtrate was evaporated in vacuo. The residue
was taken up in hydrochloric acid (20 mL of a 5N solution) was
stirred at room temperature for 72 hours, evaporated in vacuo, and
the residue was purified by RP-HPLC to afford the title compounds
3-{6-[(2-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid, [LCMS (Method A, Mobile Phase II) RT=3.65 min, MH.sup.+ 401],
and
3-{6-[(2-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid, [LCMS (Method A, Mobile Phase II) RT=3.58 min, MH.sup.+
431].
Preparation 33
(a) Methyl
3-{6-[(anilinocarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpro-
panoate
##STR00080##
To a solution of ethyl
3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (150 mg, 485
.mu.mol) in methanol (6 mL) was added phenyl isocyanate (50 .mu.L,
460 .mu.mol) and N,N-diisopropylethylamine (80 .mu.L, 459 .mu.mol).
The solution was stirred at room temperature for 48 hours, and
additional aliquots of phenyl isocyanate (10 .mu.L, 92 .mu.mol) and
N,N-diisopropylethylamine (16 .mu.L, 92 .mu.mol) were added. The
solution was stirred at room temperature for an additional 24
hours, and was then evaporated in vacuo. The residue was purified
by flash column chromatography on silica gel, eluting with a
mixture of dichloromethane and methanol (95:5) to afford the title
compound, [LCMS (Method A, Mobile Phase II) RT 5.13 min, MH.sup.+
415].
(b) Example 33b
3-{6-[(Anilinocarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
##STR00081##
A solution of methyl
3-{6-[(anilinocarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate
(90 mg, 210 .mu.mol) in a mixture of hydrochloric acid (20 mL of a
5N solution) and acetonitrile (10 mL) was stirred at room
temperature for 72 hours. The solution was evaporated in vacuo to
afford the title compound, [LCMS (Method A, Mobile Phase II)
RT=3.77 min, MH.sup.+ 401].
Example 34
3-{6-[(2-Phenoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
##STR00082##
Using the procedure of Preparation 21, the title compound (48 mg)
was prepared from ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenyl
propanoate. [LCMS (Method A, Mobile Phase I) RT=4.76 min, MH.sup.+
478].
Example 35
3-{6-[(2,6-Dimethoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
##STR00083##
Using the procedure of Preparation 21, the title compound (35 mg)
was prepared from ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenyl
propanoate and 2,6-dimethoxybenzoic acid, and purified by RP-HPLC.
[LCMS (Method A, Mobile Phase I) RT=3.71 min, MH.sup.+ 446].
Example 36
3-{6-[(1H-Indol-3-ylacetyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
##STR00084##
Using the procedure of Preparation 21, the title compound (22 mg)
was prepared from ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenyl
propanoate and indole 3-acetic acid, and purified by RP-HPLC. [LCMS
(Method A, Mobile Phase I) RT=4.08 min, MH.sup.+ 439].
Example 37
3-(6-{[3-(1H-Indol-3-yl)propanoyl]amino}-1H-benzimidazol-1-yl)-3-phenylpro-
panoic acid
##STR00085##
Using a similar procedure to that described in Preparation 21, the
title compound (25 mg) was prepared from ethyl
3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate and
3-indolepropionic acid. Hydrolysis of the intermediate ethyl
3-(6-{[3-(1H-indol-3-yl)propanoyl]amino}-1H-benzimidazol-1-yl)-3-phenylpr-
opanoate in this case was carried out using an aqueous solution of
sodium hydroxide (2N), followed by RP-HPLC purification of the
concentrated residue. [LCMS (Method A, Mobile Phase I) RT=4.29 min,
MH.sup.+ 453].
Example 38
3-Phenyl-3-[6-({[2-(phenylsulfanyl)-3-pyridinyl]carbonyl}amino)-1H-benzimi-
dazol-1-yl]propanoic acid
##STR00086##
Using the procedure of Preparation 21, the title compound (49 mg)
was prepared from ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenyl
propanoate and 2-(phenylsulfanyl)nicotinic acid, and purified by
RP-HPLC. [LCMS (Method A, Mobile Phase I) RT=4.37 min, MH.sup.+
495].
Example 39
3-(6-{[2,4-Bis(trifluoromethyl)benzoyl]amino}-1H-benzimidazol-1-yl)-3-phen-
ylpropanoic acid
##STR00087##
Using the procedure of Preparation 21, the title compound (23 mg)
was prepared from ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenyl
propanoate and 2,4-bis(trifluoromethyl)benzoic acid, and purified
by RP-HPLC. [LCMS (Method A, Mobile Phase I) RT=5.04 min, MH.sup.+
522].
Example 40
3-{6-[(2-Bromo-5-methoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropa-
noic acid
##STR00088##
Using the procedure of Preparation 21, the title compound (56 mg)
was prepared from ethyl
3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate and
2-bromo-5-methoxybenzoic acid, and purified by RP-HPLC. [LCMS
(Method A, Mobile Phase I) RT=4.35 min, MH.sup.+ 496].
Example 41
3-{6-[(2-Fluoro-6-iodobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropano-
ic acid
##STR00089##
Using the procedure of Preparation 21, the title compound (48 mg)
was prepared from ethyl
3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate and
2-fluoro-6-iodobenzoic acid. [LCMS (Method A, Mobile Phase I)
RT=4.33 min, MH.sup.+ 530].
Example 42
3-Phenyl-3-(6-{[(4-phenyl-1,2,3-thiadiazol-5-yl)carbonyl]amino}-1H-benzimi-
dazol-1-yl)propanoic acid
##STR00090##
Using the procedure of Preparation 21, the title compound (14 mg)
was prepared from ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenyl
propanoate and 4-phenyl-1,2,3-thiadiazole-5-carboxylic acid, and
purified by RP-HPLC. [LCMS (Method A, Mobile Phase I) RT=4.35 min,
MH.sup.+ 470].
Example 43
3-{6-[(3-Bromo-2,6-dimethoxybenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylp-
ropanoic acid
##STR00091##
Using the procedure of Preparation 21, the title compound (24 mg)
was prepared from ethyl
3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate and
3-bromo-2,6-dimethoxybenzoic acid, and purified by RP-HPLC. [LCMS
(Method A, Mobile Phase I) RT=4.43 min, MH.sup.+ 526].
Example 44
3-Phenyl-3-{6-[(2,3,5-trichloro-6-hydroxybenzoyl)amino]-1H-benzimidazol-1--
yl}propanoic acid
##STR00092##
Using a similar procedure to that described in Preparation 21, the
title compound (19 mg) was prepared from ethyl
3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate and
3,5,6-trichlorosalicylic acid (HATU was substituted for TBTU), and
purified by RP-HPLC. [LCMS (Method A, Mobile Phase I) RT=4.54 min,
MH.sup.+ 506].
Preparation 45
(a) Methyl (3R)-3-(2,4-dinitroanilino)-3-phenylpropanoate
##STR00093##
To a solution of 2,4-dinitrochlorobenzene (5.1 g, 25 mmol) in
methanol (60 mL) was added methyl (3R)-3-amino-3-phenylpropanoate
(3.75 g, 21 mmol, prepared according to Davies et. al., Tetrahedron
Asymm., 1991, 183) and triethylamine (2.9 mL, 21 mmol). The mixture
was brought to reflux, heating in total for 5 hours, and was then
cooled and evaporated in vacuo. The residue was purified by flash
column chromatography on silica gel, eluting with a mixture of
dichloromethane and methanol (95:5), to afford the title compound,
[LCMS (Method C, Mobile Phase I) RT=3.22 mins, MH.sup.+ 346].
(b) Methyl (3R)-3-(2-amino-4-nitroanilino)-3-phenylpropanoate
##STR00094##
To a solution of methyl
(3R)-3-(2,4-dinitroanilino)-3-phenylpropanoate (3.14 g, 9.1 mmol)
in a mixture of ethanol (100 mL) and water (10 mL) was added
ammonium formate (2.3 g, 36 mmol) and palladium on carbon (300 mg,
10% w/w Pd). The mixture was stirred at room temperature for 2
hours, then filtered through a pad of Celite.RTM., evaporated in
vacuo. The residue was purified by flash column chromatography on
silica gel, eluting with a mixture of dichloromethane and methanol
(95:5), to afford the title compound, [LCMS (Method C, Mobile Phase
I) RT=2.94 mins, MH.sup.+ 316].
(c) Methyl
(3R)-3-(5-nitro-1H-benzimidazol-1-yl)-3-phenylpropanoate
##STR00095##
To a solution of methyl
(3R)-3-(2-amino-4-nitroanilino)-3-phenylpropanoate (2.10 g, 6.7
mmol) in 2-ethoxyethanol (65 mL) was added formamidine acetate (2.8
g, 26.6 mmol), and the mixture heated to 85.degree. C. for 5 hours.
The mixture was then cooled to room temperature, evaporated in
vacuo, and the residue purified by flash column chromatography on
silica gel, eluting with a mixture of dichloromethane and methanol
(95:5) to afford a mixture of the title compound and the
corresponding 2-ethoxyethanol ester, which was used directly
without any additional purification. [LCMS (Method C, Mobile Phase
I) RT=2.86 mins (broad), MH.sup.+ 326 (Me-ester) and 384
(EtOCH.sub.2CH.sub.2-ester)].
(d) Methyl
(3R)-3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate
##STR00096##
To a solution of the crude mixture of methyl
(3R)-3-(5-nitro-1H-benzimidazol-1-yl)-3-phenylpropanoate and the
corresponding 2-ethoxyethanol ester (714 mg, ca. 2.2 mmol) in a
mixture of 1,4-dioxane (10 mL) and water (10 mL) was added
concentrated ammonia solution (0.3 mL) and sodium dithionite (3.06
g, 17.6 mmol). The solution was stirred at room temperature for 3
hours, then diluted with brine, and extracted with ethyl acetate.
The combined ethyl acetate extracts were dried over anhydrous
magnesium sulfate, filtered, and evaporated in vacuo. The residue
was purified by flash column chromatography on silica gel, gradient
eluting with a mixture of dichloromethane and methanol (95:5, then
9:1), to afford a mixture of the title compound and the
corresponding 2-ethoxyethanol ester, which was used directly
without any additional purification. [LCMS (Method C, Mobile Phase
I) RT=1.95 mins, MH.sup.+ 296 (Me-ester) and RT=2.13 mins, MH.sup.+
354 (EtOCH.sub.2CH.sub.2-ester)].
(e) Methyl
(3R)-3-{5-[(anilinocarbonyl)amino]-1H-benzimidazol-1-yl}-3-phen-
ylpropanoate
##STR00097##
To a solution of the crude mixture of methyl
(3R)-3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate and the
corresponding 2-ethoxyethanol ester (186 mg, ca. 629 .mu.mol) in
methanol (5.5 mL) was added N,N-diisopropylamine (132 .mu.L, 750
.mu.mol) and phenyl isocyanate (82 .mu.L, 750 .mu.mol). The
solution was stirred at room temperature for 12 hours, then
evaporated in vacuo, and purified by flash column chromatography on
silica gel, eluting with a mixture of dichloromethane and methanol
(95:5) to afford the title compound, [LCMS (Method C, Mobile Phase
I) RT=2.33 mins, MH.sup.+ 415].
(f) Example 45f
(3R)-3-{5-[(Anilinocarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoic
acid
##STR00098##
A solution of methyl
(3R)-3-{5-[(anilinocarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoa-
te (204 mg, 492 .mu.mol) in a mixture of tetrahydrofuran (2 mL),
acetonitrile (20 mL) and hydrochloric acid (50 mL of a 5N solution)
was stirred at room temperature for 110 hours. The solution was
evaporated in vacuo to afford the title compound, [LCMS (Method C,
Mobile Phase I) RT=2.25 min, MH.sup.+ 401.34].
Example 46
(3S)-3-(5-Nitro-1H-benzimidazol-1-yl)-3-phenylpropanoic acid
##STR00099##
Using a similar procedure to that described in Preparation 45, the
title compound (19 mg) was prepared from methyl
(3S)-3-amino-3-phenylpropanoate and 2,4-dinitrochlorobenzene, and
liberated as the free acid using a procedure similar to that
described in Preparation II. [LCMS (Method C, Mobile Phase I)
RT=2.60 min, MH.sup.+ 312].
Preparation 47
(a) Methyl
3-(1,1'-biphenyl)-4-yl-3-(2,4-dinitroanilino)propanoate
##STR00100##
To a solution of 2,4-dinitrofluorobenzene (247 mg, 847 .mu.mol) in
methanol (2 mL) was added N,N-diisopropylethylamine (147 .mu.L, 844
.mu.mol) and methyl 3-amino-3-(1,1'-biphenyl)-4-ylpropanoate (158
mg, 849 .mu.mol). The solution was stirred at room temperature for
72 hours, then evaporated in vacuo. The residue was purified by
flash column chromatography on silica gel, eluting with a mixture
of petroleum ether and dichloromethane (1:1 to 0:1), to afford the
title compound, [LCMS (Method B, Mobile Phase I) RT=3.81 min,
MH.sup.+ 422].
(b) Methyl
3-(2-amino-4-nitroanilino)-3-(1,1'-biphenyl)-4-ylpropanoate
##STR00101##
To a solution of methyl
3-(1,1'-biphenyl)-4-yl-3-(2,4-dinitroanilino)propanoate (320 mg,
760 .mu.mol) in ethanol (3 mL) was added palladium on carbon (64
mg, 10% active Pd), ammonium formate (239 mg, 3.80 mmol) and water
(1 mL). The solution was stirred at room temperature for 1.5 hour,
and was then filtered through a pad of Celite.RTM.. The filter pad
was washed with ethyl acetate, and the filtrate evaporated in
vacuo. The residue was purified by flash column chromatography on
silica gel, eluting with dichloromethane, to afford the title
compound, [LCMS (Method A, Mobile Phase I) RT=3.44 min, MH.sup.+
392].
(c) Methyl
3-(1,1'-biphenyl)-4-yl-3-(5-nitro-1H-benzimidazol-1-yl)propanoa-
te
##STR00102##
To a solution of methyl
3-(2-amino-4-nitroanilino)-3-(1,1'-biphenyl)-4-ylpropanoate (60 mg,
153 .mu.mol) in 2-ethoxyethanol (1 mL) was added formamidine
acetate (48 mg, 461 .mu.mol). The solution was heated to reflux for
6 hours, then cooled to room temperature, and evaporated in vacuo.
The residue was purified by flash column chromatography on silica
gel, eluting with dichloromethane, to afford the title compound,
[LCMS (Method A, Mobile Phase I) RT=6.11 min, MH.sup.+ 402].
(d) Example 47d
3-(1,1'-Biphenyl)-4-yl-3-(5-nitro-1H-benzimidazol-1-yl)propanoic
acid
##STR00103##
A solution of methyl
3-(1,1'-biphenyl)-4-yl-3-(5-nitro-1H-benzimidazol-1-yl)propanoate
(21 mg, 52 .mu.mol) in hydrochloric acid (10 mL of a 5N solution)
was stirred at room temperature for 48 hours. The solution was
evaporated in vacuo to afford the title compound, [LCMS (Method A,
Mobile Phase I) RT=5.63 min, MH.sup.+ 388].
Preparation 48
(a) Methyl
3-(5-amino-1H-benzimidazol-1-yl)-3-(1,1'-biphenyl)-4-ylpropanoa-
te
##STR00104##
To a solution of methyl
3-(1,1'-biphenyl)-4-yl-3-(5-nitro-1H-benzimidazol-1-yl)propanoate
(47 mg, 117 .mu.mol) in ethanol (2 mL) was added palladium on
carbon (9.0 mg, 10% active Pd), ammonium formate (37 mg, 587
.mu.mol) and water (0.5 mL). The solution was heated at reflux for
4 hours, the cooled to room temperature, and filtered through
Celite.RTM.. The filtrate was evaporated in vacuo, and the residue
was purified by flash column chromatography on silica gel, eluting
with a mixture of dichloromethane and methanol (97:3) to afford the
title compound, [LCMS (Method B, Mobile Phase I) RT=2.26 min,
MH.sup.+ 372].
(b) Example 48b
3-(5-Amino-1H-benzimidazol-1-yl)-3-(1,1'-biphenyl)-4-ylpropanoic
acid
##STR00105##
A solution of methyl
3-(5-amino-1H-benzimidazol-1-yl)-3-(1,1'-biphenyl)-4-ylpropanoate
(10 mg, 27 .mu.mol) in hydrochloric acid (10 mL of a 5N solution)
was stirred at room temperature for 48 hours. The solution was then
evaporated in vacuo to afford the title compound, [LCMS (Method A,
Mobile Phase I) RT=4.11 min, MH.sup.+ 358].
Preparation 49
(a) Methyl
3-(1,1'-biphenyl)-4-yl-3-{5-[(phenylsulfonyl)amino]-1H-benzimid-
azol-1-yl}propanoate
##STR00106##
To a solution of methyl
3-(5-amino-1H-benzimidazol-1-yl)-3-(1,1'-biphenyl)-4-ylpropanoate
(15 mg, 40 .mu.mol) in dichloromethane (500 .mu.L) was added
benzenesulfonyl chloride (6.0 .mu.L, 47 .mu.mol) and
N,N-diisopropylethylamine (8.0 .mu.L, 46 .mu.mol). The solution was
stirred at room temperature for 48 hours, and was then evaporated
in vacuo. The residue was purified by flash column chromatography
on silica gel, eluting with a mixture of dichloromethane and
methanol (96:4), to afford the title compound, [LCMS (Method A,
Mobile Phase I) RT=5.50 min, MH.sup.+ 513].
(b) Example 49b
3-[1,1'-Biphenyl]-4-yl-3-{5-[(phenylsulfonyl)amino]-1H-benzimidazol-1-yl}p-
ropanoic acid
##STR00107##
A solution of methyl
3-(1,1'-biphenyl)-4-yl-3-{5-[(phenylsulfonyl)amino]-1H-benzimidazol-1-yl}-
propanoate (12 mg, 23 .mu.mol) in hydrochloric acid (10 mL of a 5N
solution) was stirred at room temperature for 120 hours. The
solution was evaporated in vacuo to afford the title compound,
[LCMS (Method A, Mobile Phase I) RT=5.04 min, MH.sup.+ 498].
Example 50
3-(5-Nitro-1H-benzimidazol-1-yl)-3-(3-pyridinyl)propanoic acid
##STR00108##
Using the procedure of Preparation 47, the title compound, (28 mg),
was prepared from methyl 3-amino-3-(3-pyridinyl)propanoate. [LCMS
(Method A, Mobile Phase I) RT=3.09 min, MH.sup.+ 313].
Example 51
3-(5-Amino-1H-benzimidazol-1-yl)-3-(3-pyridinyl)propanoic acid
##STR00109##
Using the procedure of Preparation 48, the title compound, (27 mg),
was prepared from methyl
3-(5-nitro-1H-benzimidazol-1-yl)-3-(3-pyridinyl)propanoate. [LCMS
(Method A, Mobile Phase I) RT=1.12 min, MH.sup.+ 283].
Example 52
3-{5-[(Phenylsulfonyl)amino]-1H-benzimidazol-1-yl}-3-(3-pyridinyl)propanoi-
c acid
##STR00110##
Using the procedure of Preparation 49, the title compound, (40 mg),
was prepared from methyl
3-(5-amino-1H-benzimidazol-1-yl)-3-(3-pyridinyl)propanoate. [LCMS
(Method A, Mobile Phase I) RT=3.17 min, MH.sup.+ 423].
Example 53
3-(2-Naphthyl)-3-(5-nitro-1H-benzimidazol-1-yl)propanoic acid
##STR00111##
Using the procedure of Preparation 47, the title compound, (28 mg),
was prepared from methyl 3-amino-3-(2-naphthyl)propanoate. [LCMS
(Method A, Mobile Phase I) RT=5.27 min, MH.sup.+ 362].
Example 54
3-(5-Amino-1H-benzimidazol-1-yl)-3-(2-naphthyl)propanoic acid
##STR00112##
Using the procedure of Preparation 48, the title compound, (16 mg),
was prepared from methyl
3-(2-naphthyl)-3-(5-nitro-1H-benzimidazol-1-yl)propanoate. [LCMS
(Method A, Mobile Phase I) RT=3.62 min, MH.sup.+ 332].
Example 55
3-(2-Naphthyl)-3-{5-[(phenylsulfonyl)amino]-1H-benzimidazol-1-yl}propanoic
acid
##STR00113##
Using the procedure of Preparation 49, the title compound, (3.0
mg), was prepared from methyl
3-(5-amino-1H-benzimidazol-1-yl)-3-(2-naphthyl)propanoate. The
title compound was purified by RP-HPLC. [LCMS (Method A, Mobile
Phase I) RT=4.65 min, MH.sup.+ 472].
Example 56
3-(1-Naphthyl)-3-(5-nitro-1H-benzimidazol-1-yl)propanoic acid
##STR00114##
Using the procedure of Preparation 47, the title compound, (4.0
mg), was prepared from methyl 3-amino-3-(1-naphthyl)propanoate. The
title compound was purified by RP-HPLC. [LCMS (Method A, Mobile
Phase I) RT=5.18 min, MH.sup.+ 362].
Example 57
3-(5-Amino-1H-benzimidazol-1-yl)-3-(1-naphthyl)propanoic acid
##STR00115##
Using the procedure of Preparation 48, the title compound, (35 mg),
was prepared from methyl
3-(1-naphthyl)-3-(5-nitro-1H-benzimidazol-1-yl)propanoate. [LCMS
(Method A, Mobile Phase I) RT=3.41 min, MH.sup.+ 332].
Example 58
3-(2-Naphthyl)-3-{5-[(phenylsulfonyl)amino]-1H-benzimidazol-1-yl}propanoic
acid
##STR00116##
Using the procedure of Preparation 49, the title compound, (11 mg),
was prepared from methyl
3-(5-amino-1H-benzimidazol-1-yl)-3-(1-naphthyl)propanoate. [LCMS
(Method A, Mobile Phase I) RT=4.68 min, MH.sup.+ 472].
Example 59
3-(5-Amino-1H-benzimidazol-1-yl)-3-(4-methoxyphenyl)propanoic
acid
##STR00117##
Using a combination of Preparations 47 and 48, the title compound,
(3.0 mg), was prepared from methyl
3-amino-3-(4-methoxyphenyl)propanoate. [LCMS (Method A, Mobile
Phase I) RT=2.90 min, MH.sup.+ 312].
Example 60
3-(4-Methoxyphenyl)-3-{5-[(phenylsulfonyl)amino]-1H-benzimidazol-1-yl}prop-
anoic acid
##STR00118##
Using the procedure of Preparation 49, the title compound, (4.0
mg), was prepared from methyl
3-(5-amino-1H-benzimidazol-1-yl)-3-(4-methoxyphenyl)propanoate.
[LCMS (Method A, Mobile Phase I) RT=4.17 min, MH.sup.+ 452].
Preparation 61
(a) 4-[(3-Ethoxy-3-oxo-1-phenylpropyl)amino]-3-nitrobenzoic
acid
##STR00119##
To a solution of 4-fluoro-3-nitrobenzoic acid (185 mg, 1.00 mmol)
in DMSO (2 mL) was added ethyl-3-amino-3-phenylpropanoate (231 mg,
1.20 mmol) and potassium carbonate (166 mg, 1.20 mmol). The
suspension was heated to 100.degree. C. for 3 hours, cooled to room
temperature and diluted with water. The solution was partitioned
between ethyl acetate and dilute hydrochloric acid (2N), and the
aqueous phase separated, and extracted with ethyl acetate. The
combined organic layers were dried over anhydrous magnesium
sulfate, filtered, and evaporated in vacuo. The residue was
purified by flash column chromatography on silica gel, eluting with
a mixture of dichloromethane and methanol (96:4) to afford the
title compound, [LCMS (Method A, Mobile Phase II) RT=4.19 min,
MH.sup.+ 359].
(b) 3-Amino-4-[(3-ethoxy-3-oxo-1-phenylpropyl)amino]benzoic
acid
##STR00120##
To a solution of
4-[(3-ethoxy-3-oxo-1-phenylpropyl)amino]-3-nitrobenzoic acid, (70
mg, 196 .mu.mol) in a mixture of 1,4-dioxane, water and 0.88
ammonia solution (3:3:0.2, 6.2 mL) was added sodium dithionite (272
mg, 1.52 mmol). The resulting solution was stirred at room
temperature for 20 hours, and then extracted with ethyl acetate.
The combined extracts were dried over anhydrous magnesium sulfate,
filtered, and evaporated in vacuo, to afford the title compound,
[LCMS (Method A, Mobile Phase II) RT=3.93 min, MH.sup.+ 329].
(c) 1-(3-Ethoxy-3-oxo-1-phenylpropyl)-1H-benzimidazole-5-carboxylic
acid
##STR00121##
To a solution of
3-amino-4-[(3-ethoxy-3-oxo-1-phenylpropyl)amino]benzoic acid (57
mg, 174 .mu.mol) in 2-ethoxyethanol (1.2 mL) was added formamidine
acetate (27 mg, 259 .quadrature.mol), and the solution heated to
70.degree. C. for 1 hour. The solution was evaporated in vacuo, and
the residue purified by flash column chromatography on silica gel,
eluting with a mixture of dichloromethane and methanol (19:1) to
afford the title compound, [LCMS (Method A, Mobile Phase II)
RT=4.46 min, MH.sup.+ 339].
(d) Example 61d
1-(2-Carboxy-1-phenylethyl)-1H-benzimidazole-5-carboxylic acid
##STR00122##
A solution of
1-(3-ethoxy-3-oxo-1-phenylpropyl)-1H-benzimidazole-5-carboxylic
acid (40 mg, 118 .mu.mol) in a mixture of hydrochloric acid (10 mL
of a 5N solution) and acetonitrile (6 mL) was stirred at room
temperature for 72 hours. The solution was evaporated in vacuo to
afford the title compound, [LCMS (Method A, Mobile Phase I) RT=5.26
min, MH.sup.+ 311].
Preparation 62
(a) Ethyl
3-[5-(anilinocarbonyl)-1H-benzimidazol-1-yl]-3-phenylpropanoate
##STR00123##
To a solution of
1-(3-ethoxy-3-oxo-1-phenylpropyl)-1H-benzimidazole-5-carboxylic
acid (50 mg, 148 .mu.mol) in DMF (3 .mu.L) was added
N,N-diisopropylethylamine (50 .mu.L, 287 .mu.mol) and TBTU (57 mg,
177 .mu.mol). The solution was stirred at room temperature for 0.5
hour, aniline (20 .mu.L, 220 .mu.mol) was added, and stirring
continued at room temperature for 72 hours. The solution was
evaporated in vacuo, and the residue was purified by flash column
chromatography on silica gel, eluting with a mixture of
dichloromethane and methanol (98:2) to afford the title compound,
[LCMS (Method A, Mobile Phase I) RT=5.30 min, MH.sup.+ 414].
(b) Example 62b
3-[5-(Anilinocarbonyl)-1H-benzimidazol-1-yl]-3-phenylpropanoic
acid
##STR00124##
A solution of ethyl
3-[5-(anilinocarbonyl)-1H-benzimidazol-1-yl]-3-phenylpropanoate (27
mg, 65 .mu.mol) in a mixture of hydrochloric acid (20 mL of a 5N
solution) and acetonitrile (15 mL) was stirred at room temperature
for 96 hours. The resulting suspension was then concentrated and
filtered, and the resulting solid dried in vacuo over
P.sub.2O.sub.5 to afford the title compound, [LCMS (Method A,
Mobile Phase I) RT=4.54 min, MH.sup.+ 386].
Preparation 63
(a) Ethyl
3-phenyl-3-(5-{[4-(2-pyrazinyl)-1-piperazinyl]carbonyl}-1H-benzi-
midazol-1-yl)propanoate
##STR00125##
To a solution of
1-(3-ethoxy-3-oxo-1-phenylpropyl)-1H-benzimidazole-5-carboxylic
acid (70 mg, 207 .mu.mol) in DMF (4 mL) was added
N,N-diisopropylethylamine (40 .mu.L, 229 .mu.mol) and TBTU (80 mg,
249 .mu.mol). The solution was stirred at room temperature for 0.5
hour, 1-(2-pyrazinyl) piperazine (41 mg, 249 .mu.mol) was added,
and stirring continued at room temperature for 24 hours. The
solution was evaporated in vacuo, and the residue was purified by
flash column chromatography on silica gel, eluting with a mixture
of dichloromethane and methanol (95:5) to afford the title
compound, [LCMS (Method A, Mobile Phase I) RT=4.33 min, MH.sup.+
485].
(b) Example 63b
3-Phenyl-3-(5-{[4-(2-pyrazinyl)-1-piperazinyl]carbonyl}-1H-benzimidazol-1--
yl)propanoic acid
##STR00126##
A solution of ethyl
3-phenyl-3-(5-{[4-(2-pyrazinyl)-1-piperazinyl]carbonyl}-1H-benzimidazol-1-
-yl) propanoate (92 mg, 190 .mu.mol) in a mixture of hydrochloric
acid (20 mL of a 5N solution) and acetonitrile (15 mL) was stirred
at room temperature for 72 hours. The resulting suspension was then
evaporated in vacuo, and the residue was purified by RP-HPLC to
afford the title compound, [LCMS (Method A, Mobile Phase I) RT=3.64
min, MH.sup.+ 457].
Library Experimental Details
Generic Procedure for Sulfonamide Synthesis
To a solution of N,N-diisopropylethylamine in 1,2-dichloroethane
(30 .mu.L, 10 .mu.mol) was added ethyl
3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate in
1,2-dichloroethane (30 .mu.L, 10 .mu.mol). The appropriate sulfonyl
chloride in 1,2-dichloroethane (30 .mu.L, 10 .mu.mol) was then
added, and the mixture agitated for 48 hours. The solution was
evaporated in vacuo, and the residue taken up into acetonitrile (50
.mu.L). Hydrochloric acid (100 .mu.L of a 5N solution) was added,
and the reaction agitated for a further 48 hours. The resulting
solution was then evaporated in vacuo, to afford the title
compounds.
TABLE-US-00002 HPLC RT/min LCMS (Method A, Ex. IUPAC Name
MH.sup.+/MH.sup.- Mobile Phase II) L1
3-[5-({[4-amino-3-chlorophenyl]sulfonyl}amino)-1H- 471 3.63
benzimidazol-1-yl]-3-phenylpropanoic acid L2
3-{5-[(2,1,3-benzothiadiazol-4-ylsulfonyl)amino]-1H- 480 3.62
benzimidazol-1-yl}-3-phenylpropanoic acid L3 3-phenyl-3-[5-({[4-
506 4.27 (trifluoromethoxy)phenyl]sulfonyl}amino)-1H-
benzimidazol-1-yl]propanoic acid L4
3-(5-{[(4-bromophenyl)sulfonyl]amino}-1H-benzimidazol- 502 4.01
1-yl)-3-phenylpropanoic acid L5
3-{5-[({5-[2-(methylsulfanyl)-4-pyrimidinyl]-2- 552 4.12
thienyl}sulfonyl)amino]-1H-benzimidazol-1-yl}-3- phenylpropanoic
acid L6 3-(5-{[(2,3,4,5,6-pentamethylphenyl)sulfonyl]amino}-1H- 492
4.32 benzimidazol-1-yl)-3-phenylpropanoic acid L7
3-phenyl-3-{5-[(phenylsulfonyl)amino]-1H-benzimidazol- 422 3.66
1-yl}propanoic acid L8
3-(5-{[(4-tert-butylphenyl)sulfonyl]amino}-1H- 478 4.35
benzimidazol-1-yl)-3-phenylpropanoic acid L9
3-{5-[(1-naphthylsulfonyl)amino]-1H-benzimidazol-1-yl}- 472 4.03
3-phenylpropanoic acid L10
3-{5-[(2-naphthylsulfonyl)amino]-1H-benzimidazol-1-yl}- 472 4.07
3-phenylpropanoic acid L11
3-[5-({[5-(dimethylamino)-1-naphthyl]sulfonyl}amino)- 515 4.24
1H-benzimidazol-1-yl]-3-phenylpropanoic acid L12
3-(5-{[(4-fluorophenyl)sulfonyl]amino}-1H-benzimidazol- 440 3.77
1-yl)-3-phenylpropanoic acid L13
3-(5-{[(4-nitrophenyl)sulfonyl]amino}-1H-benzimidazol- 467 3.90
1-yl)-3-phenylpropanoic acid L14
3-[5-({[2-(acetylamino)-4-methyl-1,3-thiazol-5- 500 3.39
yl]sulfonyl}amino)-1H-benzimidazol-1-yl]-3- phenylpropanoic acid
L15 3-({[1-(2-carboxy-1-phenylethyl)-1H-benzimidazol-5- 466 2.77
yl]amino}sulfonyl)benzoic acid L16
3-[5-({[5-(3-isoxazolyl)-2-thienyl]sulfonyl}amino)-1H- 495 3.83
benzimidazol-1-yl]-3-phenylpropanoic acid L17
3-(5-{[(3,5-dimethyl-4-isoxazolyl)sulfonyl]amino}-1H- 441 3.65
benzimidazol-1-yl)-3-phenylpropanoic acid L18
3-[5-({[4-aminophenyl]sulfonyl}amino)-1H-benzimidazol- 437 3.31
1-yl]-3-phenylpropanoic acid L19
3-(5-{[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino}-1H- 426 3.02
benzimidazol-1-yl)-3-phenylpropanoic acid L20
3-phenyl-3-{5-[(2-thienylsulfonyl)amino]-1H- 428 3.64
benzimidazol-1-yl}propanoic acid L21
3-{5-[(methylsulfonyl)amino]-1H-benzimidazol-1-yl}-3- 360 3.05
phenylpropanoic acid L22
3-[5-({[4-(methylsulfonyl)phenyl]sulfonyl}amino)-1H- 500 3.53
benzimidazol-1-yl]-3-phenylpropanoic acid L23
3-phenyl-3-[5-({[2-(trifluoroacetyl)-1,2,3,4-tetrahydro-7- 573 4.07
isoquinolinyl]sulfonyl}amino)-1H-benzimidazol-1- yl]propanoic
acid
Generic Procedure for Urea Synthesis
To a solution of ethyl
3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate in
1,2-dichloroethane (30 .mu.L, 10 .mu.mol) was added the appropriate
isocyanate in 1,2-dichloroethane (30 .mu.L, 10 .mu.mol), and the
mixture agitated for 48 hours. The solution was evaporated in
vacuo, and the residue taken up into acetonitrile (50 .mu.L).
Hydrochloric acid (100 .mu.L of a 5N solution) was added, and the
reaction agitated for a further 48 hours. The resulting solution
was then evaporated in vacuo, to afford the title compounds.
TABLE-US-00003 HPLC RT/min LCMS (Method A, Mobile Ex. IUPAC Name
MH.sup.+/MH.sup.- Phase II) L24
3-[5-({[(carboxymethyl)amino]carbonyl}amino)-1H- 381 1.63
benzimidazol-1-yl]-3-phenylpropanoic acid (-ve) L25
3-(5-{[(benzylamino)carbonyl]amino}-1H- 415 3.70
benzimidazol-1-yl)-3-phenylpropanoic acid L26
3-{5-[(anilinocarbonyl)amino]-1H-benzimidazol-1- 401 3.74
yl}-3-phenylpropanoic acid L27
3-(5-{[(4-fluoroanilino)carbonyl]amino}-1H- 419 3.83
benzimidazol-1-yl)-3-phenylpropanoic acid L28
3-(5-{[(4-methoxyanilino)carbonyl]amino}-1H- 431 3.69
benzimidazol-1-yl)-3-phenylpropanoic acid L29
3-[5-({[4-(methylsulfanyl)anilino]carbonyl}amino)- 447 4.04
1H-benzimidazol-1-yl]-3-phenylpropanoic acid L30
3-(5-{[(4-nitroanilino)carbonyl]amino}-1H- 446 3.96
benzimidazol-1-yl)-3-phenylpropanoic acid L31 3-phenyl-3-[5-({[4-
469 4.36 (trifluoromethyl)anilino]carbonyl}amino)-1H-
benzimidazol-1-yl]propanoic acid L32
3-(5-{[(3,4-dimethylanilino)carbonyl]amino}-1H- 429 4.13
benzimidazol-1-yl)-3-phenylpropanoic acid L33
3-[5-({[4-(benzyloxy)anilino]carbonyl}amino)-1H- 507 4.45
benzimidazol-1-yl]-3-phenylpropanoic acid L34
3-[5-({[(2,6-dichloro-4- 470 4.01
pyridinyl)amino]carbonyl}amino)-1H-benzimidazol-
1-yl]-3-phenylpropanoic acid L35
3-(5-{[(cyclohexylamino)carbonyl]amino}-1H- 407 3.80
benzimidazol-1-yl)-3-phenylpropanoic acid L36
3-phenyl-3-{5-[({[2-(2- 435 3.77
thienyl)ethyl]amino}carbonyl)amino]-1H- benzimidazol-1-yl}propanoic
acid
Generic Procedure for Amide Synthesis
To a solution of the appropriate carboxylic acid in NMP (60 .mu.L,
20 .mu.mol) was added N,N-diisopropylethylamine in NMP (36 .mu.L,
20 .mu.mol) and HATU in NMP (36 .mu.L, 12 .mu.mol). A solution of
either ethyl 3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate or
ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate in NMP
(30 .mu.L, 10 .mu.mol) was then added, and the resulting solution
agitated for 90 hours. The solution was evaporated in vacuo, and
the residue taken up in acetonitrile (120 .mu.L). Hydrochloric acid
(180 .mu.L of a 5N solution) was added, and the solution agitated
for a further 72 hours. The solution was evaporated in vacuo to
afford the title compounds.
(* denotes isomers formed)
TABLE-US-00004 LCMS HPLC LCMS Mobile Ex. IUPAC Name
MH.sup.+/MH.sup.- RT/min Method Phase L37
3-phenyl-3-{5-[(2-quinolinylcarbonyl)amino]- 437 2.29 B II
1H-benzimidazol-1-yl}propanoic acid L38
3-{5-[(3-isoquinolinylcarbonyl)amino]-1H- 437 2.20 B II
benzimidazol-1-yl}-3-phenylpropanoic acid L39 3-phenyl-3-{5-[(2-
438 2.07 B II quinoxalinylcarbonyl)amino]-1H-
benzimidazol-1-yl}propanoic acid L40
3-{5-[(1-isoquinolinylcarbonyl)amino]-1H- 437 2.16 B II
benzimidazol-1-yl}-3-phenylpropanoic acid L41
3-{5-[(2,3-dihydro-1H-indol-2- 427 2.08, B II
ylcarbonyl)amino]-1H-benzimidazol-1-yl}-3- 2.22* phenylpropanoic
acid L42 3-phenyl-3-{5-[(2- 438 1.76 B II
quinoxalinylcarbonyl)amino]-1H- benzimidazol-1-yl}propanoic acid
L43 3-phenyl-3-{5-[(2-pyrazinylcarbonyl)amino]- 388 1.66 B II
1H-benzimidazol-1-yl}propanoic acid L44
3-phenyl-3-{5-[(3-pyridinylcarbonyl)amino]- 387 1.56 B II
1H-benzimidazol-1-yl}propanoic acid L45
3-[5-(isonicotinoylamino)-1H-benzimidazol- 387 1.59 B II
1-yl]-3-phenylpropanoic acid L46 3-(5-{[(2-hydroxy-3- 403 1.56 B II
pyridinyl)carbonyl]amino}-1H-benzimidazol- 1-yl)-3-phenylpropanoic
acid L47 3-{5-[(1H-indol-2-ylcarbonyl)amino]-1H- 425 2.21 B II
benzimidazol-1-yl}-3-phenylpropanoic acid L48
3-{5-[(1H-indol-3-ylcarbonyl)amino]-1H- 425 1.96 B II
benzimidazol-1-yl}-3-phenylpropanoic acid L49
3-{5-[(3-nitrobenzoyl)amino]-1H- 431 2.05 B II
benzimidazol-1-yl}-3-phenylpropanoic acid L50
3-phenyl-3-{5-[(3-pyridinylacetyl)amino]-1H- 401 1.56 B II
benzimidazol-1-yl}propanoic acid L51
3-{5-[(1H-imidazol-4-ylacetyl)amino]-1H- 390 1.20, B II
benzimidazol-1-yl}-3-phenylpropanoic acid 1.27* L52
3-(5-{[(2E)-3-(3-nitrophenyl)-2- 457 2.24 B II
propenoyl]amino}-1H-benzimidazol-1-yl)-3- phenylpropanoic acid L53
3-(5-{[3-(1H-benzimidazol-2- 454 1.80 B II
yl)propanoyl]amino}-1H-benzimidazol-1-yl)- 3-phenylpropanoic acid
L54 3-phenyl-3-(5-{[3-(3,4,5- 505 1.97 B II
trimethoxyphenyl)propanoyl]amino}-1H- benzimidazol-1-yl)propanoic
acid L55 3-{5-[(1H-indol-3-ylacetyl)amino]-1H- 439 2.00 B II
benzimidazol-1-yl}-3-phenylpropanoic acid L56
3-(5-{[3-(1H-indol-3-yl)propanoyl]amino}- 453 2.09 B II
1H-benzimidazol-1-yl)-3-phenylpropanoic acid L57
3-phenyl-3-{5-[(2-pyridinylcarbonyl)amino]- 387 1.87 B II
1H-benzimidazol-1-yl}propanoic acid L58
3-(5-{[4-(1H-indol-3-yl)butanoyl]amino}-1H- 467 2.33 B II
benzimidazol-1-yl)-3-phenylpropanoic acid L59 3-(5-{[(5-methyl-2-
402 1.74 B II pyrazinyl)carbonyl]amino}-1H-benzimidazol-
1-yl)-3-phenylpropanoic acid L60
3-(5-{[(5-methyl-2-phenyl-2H-1,2,3-triazol-4- 468 2.45 B II
yl)carbonyl]amino}-1H-benzimidazol-1-yl)-3- phenylpropanoic acid
L61 3-(5-{[(4-oxo-4,5,6,7-tetrahydro-1- 444 2.01 B II
benzofuran-3-yl)carbonyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L62
3-[5-({[2-(methylsulfanyl)-3- 433 1.85 B II
pyridinyl]carbonyl}amino)-1H-benzimidazol- 1-yl]-3-phenylpropanoic
acid L63 3-[5-({[3-chloro-4-(isopropylsulfonyl)-2- 532 2.08 B II
thienyl]carbonyl}amino)-1H-benzimidazol-1- yl]-3-phenylpropanoic
acid L64 3-(5-{[(6-oxo-1,4,5,6-tetrahydro-3- 406 1.50 B II
pyridazinyl)carbonyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L65
3-[5-({[2-(2,3-dihydro-1,4-benzodioxin-2-yl)- 528 2.44 B II
1,3-thiazol-4-yl]carbonyl}amino)-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L66
3-[5-({(2E)-3-[3-nitro-4-(1- 526 2.49 B II
pyrrolidinyl)phenyl]-2-propenoyl}amino)-1H-
benzimidazol-1-yl]-3-phenylpropanoic acid L67 3-(5-{[3-(2- 519 2.76
B II oxocyclododecyl)propanoyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L68
3-(5-{[(1-tert-butyl-3-methyl-1H-pyrazol-5- 446 2.00 B II
yl)carbonyl]amino}-1H-benzimidazol-1-yl)-3- phenylpropanoic acid
L69 3-(5-{[(2Z)-2-(3-oxo-2-benzofuran-1(3H)- 454 1.99 B II
ylidene)ethanoyl]amino}-1H-benzimidazol-1- yl)-3-phenylpropanoic
acid L70 3-{5-[(1-benzothien-2-ylcarbonyl)amino]-1H- 442 2.29 B II
benzimidazol-1-yl}-3-phenylpropanoic acid L71 3-phenyl-3-(5-{[4-
470 2.37 B II (trifluoromethoxy)benzoyl]amino}-1H-
benzimidazol-1-yl)propanoic acid L72 3-(5-{[(5-chloro-2-hydroxy-3-
437 1.74 B II pyridinyl)carbonyl]amino}-1H-benzimidazol-
1-yl)-3-phenylpropanoic acid L73 3-(5-{[(2E)-4-oxo-4-(2,3,4,5,6-
510 2.62 B II pentamethylphenyl)-2-butenoyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L74
3-(5-{[(6-bromo-2-oxo-2H-chromen-3- 534 2.47 B II
yl)carbonyl]amino}-1H-benzimidazol-1-yl)-3- phenylpropanoic acid
L75 3-phenyl-3-(5-{[4- 480(-ve) 1.89 B II
(trifluoroacetyl)benzoyl]amino}-1H- benzimidazol-1-yl)propanoic
acid L76 3-[5-({[(4- 477 1.99 B II
chlorobenzoyl)amino]acetyl}amino)-1H-
benzimidazol-1-yl]-3-phenylpropanoic acid L77
3-(5-{[(2,7-dimethylpyrazolo[1,5- 455 1.77 B II
a]pyrimidin-6-yl)carbonyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L78
3-(5-{[(4-acetyl-5-methyl-2-oxo-2,3-dihydro- 462 1.71 B II
1H-pyrrol-3-yl)acetyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L79
3-phenyl-3-(5-{[(4-phenyl-1,2,3-thiadiazol-5- 470 2.13 B II
yl)carbonyl]amino}-1H-benzimidazol-1- yl)propanoic acid L80
3-[5-({[1-(4-chlorobenzyl)-5-oxo-3- 517 2.11 B II
pyrrolidinyl]carbonyl}amino)-1H-
benzimidazol-1-yl]-3-phenylpropanoic acid L81 3-(5-{[({[(Z)-1-(4-
491 2.47 B II chlorophenyl)ethylidene]amino}oxy)acetyl]amino}-
1H-benzimidazol-1-yl)-3- phenylpropanoic acid L82
3-phenyl-3-{5-[(1,2,3-thiadiazol-4- 394 1.70 B II
ylcarbonyl)amino]-1H-benzimidazol-1- yl}propanoic acid L83
3-(5-{[(5-chloro-1-benzothien-3- 490 2.44 B II
yl)acetyl]amino}-1H-benzimidazol-1-yl)-3- phenylpropanoic acid L84
3-[5-({[5-chloro-2-(methylsulfanyl)-4- 468 2.12 B II
pyrimidinyl]carbonyl}amino)-1H-
benzimidazol-1-yl]-3-phenylpropanoic acid L85
3-[5-({[1-(2-furylmethyl)-5-oxo-3- 473 1.78 B II
pyrrolidinyl]carbonyl}amino)-1H-
benzimidazol-1-yl]-3-phenylpropanoic acid L86
3-(5-{[(3-tert-butyl-1-methyl-1H-pyrazol-5- 446 2.19 B II
yl)carbonyl]amino}-1H-benzimidazol-1-yl)-3- phenylpropanoic acid
L87 3-(5-{[(5-oxo-2- 393 1.30 B II pyrrolidinyl)carbonyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L88
3-(5-{[(2,5-dimethoxyphenyl)acetyl]amino}- 460 2.04 B II
1H-benzimidazol-1-yl)-3-phenylpropanoic acid L89
3-[5-({[2-(4-methylphenoxy)-3- 494 2.30 B II
pyridinyl]carbonyl}amino)-1H-benzimidazol- 1-yl]-3-phenylpropanoic
acid L90 3-[5-(2-methyl-6-nitro-4-oxo-3(4H)- 470 2.03 B II
quinazolinyl)-1H-benzimidazol-1-yl]-3- phenylpropanoic acid L91
3-(5-{[(3-methoxyphenyl)acetyl]amino}-1H- 430 2.00 B II
benzimidazol-1-yl)-3-phenylpropanoic acid L92
3-(5-{[(4-methoxyphenyl)acetyl]amino}-1H- 430 1.99 B II
benzimidazol-1-yl)-3-phenylpropanoic acid L93
3-(5-{[(2-methoxyphenyl)acetyl]amino}-1H- 430 2.04 B II
benzimidazol-1-yl)-3-phenylpropanoic acid L94 3-(5-{[(2-phenoxy-3-
479 2.12 B II pyridinyl)carbonyl]amino}-1H-benzimidazol-
1-yl)-3-phenylpropanoic acid L95
3-[5-({2-[4-(aminocarbonyl)phenoxy]-2- 487 1.77 B II
methylpropanoyl}amino)-1H-benzimidazol-1- yl]-3-phenylpropanoic
acid L96 3-phenyl-3-{5-[(1,2,3,4-tetrahydro-2- 440 2.30 B II
naphthalenylcarbonyl)amino]-1H- benzimidazol-1-yl}propanoic acid
L97 3-(5-{[(3,5-dimethyl-4- 405 1.74 B II
isoxazolyl)carbonyl]amino}-1H- benzimidazol-1-yl)-3-phenylpropanoic
acid L98 3-phenyl-3-{5-[(1H-pyrrol-2- 375 1.79 B II
ylcarbonyl)amino]-1H-benzimidazol-1- yl}propanoic acid L99
3-[5-({[(2S)-5- 393 1.30 B II oxopyrrolidinyl]carbonyl}amino)-1H-
benzimidazol-1-yl]-3-phenylpropanoic acid L100
3-phenyl-3-[5-({[(3S,4R,5S)-3,4,5-trihydroxy- 438 1.10 B II
1-cyclohexen-1-yl]carbonyl}amino)-1H- benzimidazol-1-yl]propanoic
acid L101 3-{5-[(cyclohexylacetyl)amino]-1H- 406 2.20 B II
benzimidazol-1-yl}-3-phenylpropanoic acid L102
3-phenyl-3-(5-{[4-(1H-pyrrol-1- 451 2.34 B II
yl)benzoyl]amino}-1H-benzimidazol-1- yl)propanoic acid L103
3-(5-{[(2,4-dihydroxy-5- 420 1.46 B II
pyrimidinyl)carbonyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L104
3-(5-{[2-(1,3-dioxo-1,3-dihydro-2H-isoindol- 483 2.02 B II
2-yl)propanoyl]amino}-1H-benzimidazol-1- yl)-3-phenylpropanoic acid
L105 3-(5-{[3-(1,3-dioxo-1,3-dihydro-2H-isoindol- 483 1.90 B II
2-yl)propanoyl]amino}-1H-benzimidazol-1- yl)-3-phenylpropanoic acid
L106 3-[5-({[1-(4- 488 2.59 B II
chlorophenyl)cyclopentyl]carbonyl}amino)-
1H-benzimidazol-1-yl]-3-phenylpropanoic acid L107
3-(5-{[(4-oxo-2-thioxo-1,3-thiazolidin-3- 455 1.85 B II
yl)acetyl]amino}-1H-benzimidazol-1-yl)-3- phenylpropanoic acid L108
3-{5-[([1,1'-biphenyl]-4-ylacetyl)amino]-1H- 476 2.48 B II
benzimidazol-1-yl}-3-phenylpropanoic acid L109
3-(5-{[(6-methoxy-3-oxo-2,3-dihydro-1H- 485 1.90 B II
inden-1-yl)acetyl]amino}-1H-benzimidazol-1- yl)-3-phenylpropanoic
acid L110 3-{5-[(9H-fluoren-9-ylacetyl)amino]-1H- 488 2.50 B II
benzimidazol-1-yl}-3-phenylpropanoic acid L111
3-(5-{[(9-oxo-9H-fluoren-1- 489 2.39 B II
yl)carbonyl]amino}-1H-benzimidazol-1-yl)-3- phenylpropanoic acid
L112 3-(5-{[(2-nitrophenyl)acetyl]amino}-1H- 445 2.00 B II
benzimidazol-1-yl)-3-phenylpropanoic acid L113
3-(5-{[(4-nitrophenyl)acetyl]amino}-1H- 445 2.04 B II
benzimidazol-1-yl)-3-phenylpropanoic acid L114
3-{5-[(9-anthrylcarbonyl)amino]-1H- 486 2.43 B II
benzimidazol-1-yl}-3-phenylpropanoic acid L115
3-(5-{[(2-methylphenyl)acetyl]amino}-1H- 414 2.08 B II
benzimidazol-1-yl)-3-phenylpropanoic acid L116
3-(5-{[(2,6-dioxo-1,2,3,6-tetrahydro-4- 421 2.50 A II
pyrimidinyl)carbonyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L117
3-(5-{[(4-methylphenyl)acetyl]amino}-1H- 414 3.68 A II
benzimidazol-1-yl)-3-phenylpropanoic acid L118
3-{5-[(3-methylbenzoyl)amino]-1H- 400 3.63 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L119
3-phenyl-3-{5-[(4-vinylbenzoyl)amino]-1H- 413 3.80 A II
benzimidazol-1-yl}propanoic acid L120
3-{5-[(4-methylbenzoyl)amino]-1H- 400 3.60 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L121
3-{5-[(2-methylbenzoyl)amino]-1H- 400 3.47 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L122
3-(5-{[(3-methylphenyl)acetyl]amino}-1H- 414 3.70 A II
benzimidazol-1-yl)-3-phenylpropanoic acid L123
3-(5-{[(3-nitrophenyl)acetyl]amino}-1H- 445 3.58 A II
benzimidazol-1-yl)-3-phenylpropanoic acid L124
3-{5-[(4-bromobenzoyl)amino]-1H- 464 3.81 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L125
3-phenyl-3-{5-[(9H-xanthen-9- 490 4.10 A II
ylcarbonyl)amino]-1H-benzimidazol-1- yl}propanoic acid L126
3-{5-[(2-phenoxypropanoyl)amino]-1H- 430 3.69 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L127
3-(5-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2- 469 3.28 A II
yl)acetyl]amino}-1H-benzimidazol-1-yl)-3- phenylpropanoic acid L128
3-{5-[(1,3-benzodioxol-5-ylcarbonyl)amino]- 430 3.37 A II
1H-benzimidazol-1-yl}-3-phenylpropanoic acid L129
3-phenyl-3-{5-[(phenylacetyl)amino]-1H- 400 3.42 A II
benzimidazol-1-yl}propanoic acid L130
3-{5-[(bicyclo[2.2.1]hept-5-en-2- 402 3.63 A II
ylcarbonyl)amino]-1H-benzimidazol-1-yl}-3- phenylpropanoic acid
L131 3-(5-{[hydroxy(phenyl)acetyl]amino}-1H- 416 3.12 A II
benzimidazol-1-yl)-3-phenylpropanoic acid L132
3-(5-{[(2-naphthyloxy)acetyl]amino}-1H- 466 4.08 A II
benzimidazol-1-yl)-3-phenylpropanoic acid L133 3-phenyl-3-(5-{[(1-
454 4.04 A II phenylcyclopentyl)carbonyl]amino}-1H-
benzimidazol-1-yl)propanoic acid L134
3-phenyl-3-{5-[(2-sulfanylbenzoyl)amino]- 416 3.53 A II
1H-benzimidazol-1-yl}propanoic acid L135
3-(5-{[cyclopentyl(phenyl)acetyl]amino}-1H- 468 4.25 A II
benzimidazol-1-yl)-3-phenylpropanoic acid L136
3-{5-[(4-tert-butylbenzoyl)amino]-1H- 442 4.25 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L137
3-{5-[(1-adamantylcarbonyl)amino]-1H- 444 4.09 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L138
3-{5-[(4-methoxybenzoyl)amino]-1H- 416 3.42 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L139
3-{5-[(4-cyclohexylbenzoyl)amino]-1H- 468 4.65 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L140
3-[5-(1-naphthoylamino)-1H-benzimidazol-1- 437 3.73 A II
yl]-3-phenylpropanoic acid L141
3-[5-(benzoylamino)-1H-benzimidazol-1-yl]- 387 3.31 A II
3-phenylpropanoic acid L142 3-(5-{[(2E)-3-(4-bromophenyl)-2- 492
4.09 A II propenoyl]amino}-1H-benzimidazol-1-yl)-3- phenylpropanoic
acid L143 3-{5-[(3-bromo-4-methoxybenzoyl)amino]- 496 3.79 A II
1H-benzimidazol-1-yl}-3-phenylpropanoic acid L144
3-{5-[(4-butylbenzoyl)amino]-1H- 443 4.32 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L145
3-(5-{[4-(dimethylamino)benzoyl]amino}- 429 3.58 A II
1H-benzimidazol-1-yl)-3-phenylpropanoic acid L146
3-(5-{[(4-bromo-1-ethyl-3-methyl-1H- 498 3.58 A II
pyrazol-5-yl)carbonyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L147
3-{5-[(4-nitrobenzoyl)amino]-1H- 431 3.66 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L148
3-(5-{[(2-cyclopropyl-4- 477 3.72 A II
quinolinyl)carbonyl]amino}-1H- benzimidazol-1-yl)-3-phenylpropanoic
acid L149 3-phenyl-3-[5-({[2-(2-thienyl)-4- 519 4.15 A II
quinolinyl]carbonyl}amino)-1H- benzimidazol-1-yl]propanoic acid
L150 3-{5-[(3,5-dinitrobenzoyl)amino]-1H- 476 3.80 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L151
3-phenyl-3-{5-[(3-phenyl-2- 410 3.74 A II
propynoyl)amino]-1H-benzimidazol-1- yl}propanoic acid L152
3-{5-[(4-fluoro-1-naphthoyl)amino]-1H- 454 3.86 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L153
3-(5-{[(7-methyl-2-phenyl-4- 527 4.33 A II
quinolinyl)carbonyl]amino}-1H- benzimidazol-1-yl)-3-phenylpropanoic
acid L154 3-(5-{[(5-bromo-4-methoxy-3- 500 3.96 A II
thienyl)carbonyl]amino}-1H-benzimidazol-1- yl)-3-phenylpropanoic
acid L155 3-{5-[(4-[1,1'-biphenyl]-4-yl-4- 518 4.25 A II
oxobutanoyl)amino]-1H-benzimidazol-1-yl}- 3-phenylpropanoic acid
L156 3-{5-[(1-cyclohexen-1-ylcarbonyl)amino]-1H- 390 3.50 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L157
3-(5-{[(4-bromophenyl)acetyl]amino}-1H- 480 3.83 A II
benzimidazol-1-yl)-3-phenylpropanoic acid L158
3-(5-{[2-(methylsulfanyl)benzoyl]amino}-1H- 432 3.48 A II
benzimidazol-1-yl)-3-phenylpropanoic acid L159
3-(5-{[(2E)-3-(5-bromo-2-ethoxyphenyl)-2- 536 4.31 A II
propenoyl]amino}-1H-benzimidazol-1-yl)-3- phenylpropanoic acid L160
3-(5-{[4-(methylsulfonyl)benzoyl]amino}- 465 3.17 A II
1H-benzimidazol-1-yl)-3-phenylpropanoic acid L161 3-(5-{[2-nitro-4-
499 3.86 A II (trifluoromethyl)benzoyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L162
3-{5-[([1,1'-biphenyl]-4-ylcarbonyl)amino]- 462 4.17 A II
1H-benzimidazol-1-yl}-3-phenylpropanoic acid L163
3-{5-[(4-benzoylbenzoyl)amino]-1H- 490 3.94 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L164 3-phenyl-3-(5-{[4-
454 3.93 A II (trifluoromethyl)benzoyl]amino}-1H-
benzimidazol-1-yl)propanoic acid L165
3-{5-[(4-acetylbenzoyl)amino]-1H- 428 3.27 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L166
3-{5-[(4-cyanobenzoyl)amino]-1H- 411 3.38 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L167 3-(5-{[2,4- 522 4.08
A II bis(trifluoromethyl)benzoyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L168 3-phenyl-3-(5-{[3-
454 3.91 A II (trifluoromethyl)benzoyl]amino}-1H-
benzimidazol-1-yl)propanoic acid L169
3-{5-[(3-cyanobenzoyl)amino]-1H- 412 3.37 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L170
3-{5-[(1H-benzimidazol-5-ylcarbonyl)amino]- 426 2.89 A II
1H-benzimidazol-1-yl}-3-phenylpropanoic acid L171
3-{5-[(diphenylacetyl)amino]-1H- 477 4.10 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L172
3-{5-[(2-hydroxybenzoyl)amino]-1H- 402 3.57 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L173
3-{5-[(4-ethylbenzoyl)amino]-1H- 414 3.84 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L174 3-{5-[(3-bromo-2,6-
526 3.68 A II dimethoxybenzoyl)amino]-1H-benzimidazol-
1-yl}-3-phenylpropanoic acid L175 3-{5-[(4-bromo-2,3,5,6- 538 4.01
A II tetrafluorobenzoyl)amino]-1H-benzimidazol-
1-yl}-3-phenylpropanoic acid L176
3-{5-[(5-bromo-2-furoyl)amino]-1H- 454 3.49 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L177
3-{5-[(3-iodobenzoyl)amino]-1H- 512 3.90 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L178
3-{5-[(2-formylbenzoyl)amino]-1H- 415 3.10 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L179
3-{5-[(2-bromobenzoyl)amino]-1H- 464 3.45 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L180
3-{5-[(3-bromobenzoyl)amino]-1H- 466 3.80 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L181 3-(5-{[(5-bromo-3-
465 3.31 A II pyridinyl)carbonyl]amino}-1H-benzimidazol-
1-yl)-3-phenylpropanoic acid L182
3-(5-{[(5-bromo-2-thienyl)carbonyl]amino}- 472 3.82 A II
1H-benzimidazol-1-yl)-3-phenylpropanoic acid L183
3-{5-[(2-bromo-5-methoxybenzoyl)amino]- 494 3.58 A II
1H-benzimidazol-1-yl}-3-phenylpropanoic acid L184
3-{5-[(4-bromo-2-methylbenzoyl)amino]-1H- 478 3.87 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L185
3-{5-[(4-bromo-2-chlorobenzoyl)amino]-1H- 500 3.90 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L186
3-(5-{[(2E)-3-(3-bromo-4-fluorophenyl)-2- 508 4.12 A II
propenoyl]amino}-1H-benzimidazol-1-yl)-3- phenylpropanoic acid L187
3-(5-{[(2E)-3-(6-bromo-1,3-benzodioxol-5- 534 3.96 A II
yl)-2-propenoyl]amino}-1H-benzimidazol-1- yl)-3-phenylpropanoic
acid L188 3-phenyl-3-[5-({[2-(phenylsulfanyl)-3- 495 3.63 A II
pyridinyl]carbonyl}amino)-1H-benzimidazol- 1-yl]propanoic acid L189
3-{5-[(2-hydroxy-5-nitrobenzoyl)amino]-1H- 447 2.88 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L190
3-{5-[(2-hydroxy-3-methoxybenzoyl)amino]- 433 3.40 A II
1H-benzimidazol-1-yl}-3-phenylpropanoic acid L191
3-(5-{[(4-hydroxy-3- 446 2.88 A II methoxyphenyl)acetyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L192
3-{5-[(2,5-dihydroxybenzoyl)amino]-1H- 419 3.09 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L193
3-{5-[(2-hydroxy-3-methylbenzoyl)amino]- 416 3.96 A II
1H-benzimidazol-1-yl}-3-phenylpropanoic acid L194
3-{5-[(3-hydroxy-4-methylbenzoyl)amino]- 416 33.8 A II
1H-benzimidazol-1-yl}-3-phenylpropanoic acid L195
3-(5-{[(3-hydroxy-4- 447 3.10 A II methoxyphenyl)acetyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L196
3-(5-{[(4,7-dimethylpyrazolo[5,1- 456 3.44 A II
c][1,2,4]triazin-3-yl)carbonyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L197 3-(5-{[3-(2,4- 416
3.39 A II dihydroxyphenyl)propanoyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L198
3-(5-{[(3,5-ditert-butyl-4- 528 4.47 A II
hydroxyphenyl)acetyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L199
3-(5-{[(6-hydroxy-2,5,7,8-tetramethyl-3,4- 514 3.90 A II
dihydro-2H-chromen-2-yl)carbonyl]amino}-
1H-benzimidazol-1-yl)-3-phenylpropanoic acid L200
3-{5-[(3,5-dichloro-2- 470 3.49 A II
hydroxybenzoyl)amino]-1H-benzimidazol-1- yl}-3-phenylpropanoic acid
L201 3-phenyl-3-{5-[(2,4,6- 434 3.01 A II
trihydroxybenzoyl)amino]-1H-benzimidazol- 1-yl}propanoic acid L202
3-{5-[(2-hydroxybenzoyl)amino]-1H- 402 3.56 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L203
3-phenyl-3-{5-[(2,3,5-trichloro-6- 504 3.55 A II
hydroxybenzoyl)amino]-1H-benzimidazol-1- yl}propanoic acid L204
3-{5-[(5-chloro-2-hydroxybenzoyl)amino]- 437 3.85 A II
1H-benzimidazol-1-yl}-3-phenylpropanoic acid L205
3-{5-[(5-bromo-2-hydroxybenzoyl)amino]- 480 (-ve) 3.92 A II
1H-benzimidazol-1-yl}-3-phenylpropanoic acid L206
3-{5-[(2-hydroxy-4-methylbenzoyl)amino]- 416 3.80 A II
1H-benzimidazol-1-yl}-3-phenylpropanoic acid L207
3-(5-{[(3,4-dihydroxyphenyl)acetyl]amino}- 433 2.60 A II
1H-benzimidazol-1-yl)-3-phenylpropanoic acid L208
3-{5-[(2-fluoro-6-iodobenzoyl)amino]-1H- 530 3.57 A II
benzimidazol-1-yl}-3-phenylpropanoic acid L209
3-phenyl-3-{6-[(2-quinolinylcarbonyl)amino]- 437 2.39 B I
1H-benzimidazol-1-yl}propanoic acid L210
3-{6-[(3-isoquinolinylcarbonyl)amino]-1H- 437 2.31 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L211 3-phenyl-3-{6-[(2-
438 2.15 B I quinoxalinylcarbonyl)amino]-1H-
benzimidazol-1-yl}propanoic acid L212
3-{6-[(1-isoquinolinylcarbonyl)amino]-1H- 438 2.29 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L213
3-{6-[(2,3-dihydro-1H-indol-2- 426 2.16 B I
ylcarbonyl)amino]-1H-benzimidazol-1-yl}-3- phenylpropanoic acid
L214 3-phenyl-3-{6-[(2- 438 1.75 B I
quinoxalinylcarbonyl)amino]-1H- benzimidazol-1-yl}propanoic acid
L215 3-phenyl-3-{6-[(2-pyrazinylcarbonyl)amino]- 388 1.62 B I
1H-benzimidazol-1-yl}propanoic acid L216
3-phenyl-3-{6-[(3-pyridinylcarbonyl)amino]- 387 1.42 B I
1H-benzimidazol-1-yl}propanoic acid L217
3-[6-(isonicotinoylamino)-1H-benzimidazol- 387 1.37 B I
1-yl]-3-phenylpropanoic acid L218 3-(6-{[(2-hydroxy-3- 403 1.56 B I
pyridinyl)carbonyl]amino}-1H-benzimidazol- 1-yl)-3-phenylpropanoic
acid L219 3-{6-[(1H-indol-2-ylcarbonyl)amino]-1H- 425 2.23 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L220
3-{6-[(1H-indol-3-ylcarbonyl)amino]-1H- 425 1.97 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L221
3-{6-[(3-nitrobenzoyl)amino]-1H- 431 2.14 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L222
3-(6-{[(2E)-3-(1H-indol-3-yl)-2- 451 2.35 B I
propenoyl]amino}-1H-benzimidazol-1-yl)-3- phenylpropanoic acid L223
3-(6-{[(2E)-3-(3-nitrophenyl)-2- 457 2.23 B I
propenoyl]amino}-1H-benzimidazol-1-yl)-3- phenylpropanoic acid L224
3-(6-{[3-(1H-benzimidazol-2- 454 1.33 B I
yl)propanoyl]amino}-1H-benzimidazol-1-yl)- 3-phenylpropanoic acid
L225 3-phenyl-3-(6-{[3-(3,4,5- 504 1.92 B I
trimethoxyphenyl)propanoyl]amino}-1H- benzimidazol-1-yl)propanoic
acid L226 3-{6-[(1H-indol-3-ylacetyl)amino]-1H- 439 2.03 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L227
3-(6-{[3-(1H-indol-3-yl)propanoyl]amino}- 453 2.15 B I
1H-benzimidazol-1-yl)-3-phenylpropanoic acid
L228 3-phenyl-3-{6-[(2-pyridinylcarbonyl)amino]- 387 1.89 B I
1H-benzimidazol-1-yl}propanoic acid L229 3-(6-{[(5-methyl-2- 402
1.75 B I pyrazinyl)carbonyl]amino}-1H-benzimidazol-
1-yl)-3-phenylpropanoic acid L230
3-(6-{[(5-methyl-2-phenyl-2H-1,2,3-triazol-4- 467 2.63 B I
yl)carbonyl]amino}-1H-benzimidazol-1-yl)-3- phenylpropanoic acid
L231 3-(6-{[(4-oxo-4,5,6,7-tetrahydro-1- 444 2.05 B I
benzofuran-3-yl)carbonyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L232
3-[6-({[2-(methylsulfanyl)-3- 433 1.90 B I
pyridinyl]carbonyl}amino)-1H-benzimidazol- 1-yl]-3-phenylpropanoic
acid L233 3-[6-({[3-chloro-4-(isopropylsulfonyl)-2- 533 2.13 B I
thienyl]carbonyl}amino)-1H-benzimidazol-1- yl]-3-phenylpropanoic
acid L234 3-(6-{[(6-oxo-1,4,5,6-tetrahydro-3- 406 1.46 B I
pyridazinyl)carbonyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L235
3-[6-({[2-(2,3-dihydro-1,4-benzodioxin-2-yl)- 527 2.45, B I
1,3-thiazol-4-yl]carbonyl}amino)-1H- 2.61*
benzimidazol-1-yl]-3-phenylpropanoic acid L236
3-[6-({(2E)-3-[3-nitro-4-(1- 526 2.59, B I
pyrrolidinyl)phenyl]-2-propenoyl}amino)-1H- 2.73*
benzimidazol-1-yl]-3-phenylpropanoic acid L237 3-(6-{[3-(2- 519
2.88 B I oxocyclododecyl)propanoyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L238
3-(6-{[(1-tert-butyl-3-methyl-1H-pyrazol-5- 446 2.12 B I
yl)carbonyl]amino}-1H-benzimidazol-1-yl)-3- phenylpropanoic acid
L239 3-(6-{[(2Z)-2-(3-oxo-2-benzofuran-1(3H)- 454 2.00 B I
ylidene)ethanoyl]amino}-1H-benzimidazol-1- yl)-3-phenylpropanoic
acid L240 3-{6-[(1-benzothien-2-ylcarbonyl)amino]-1H- 442 2.45 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L241 3-phenyl-3-(6-{[4-
470 2.51 B I (trifluoromethoxy)benzoyl]amino}-1H-
benzimidazol-1-yl)propanoic acid L242 3-(6-{[(5-chloro-2-hydroxy-3-
437 1.87 B I pyridinyl)carbonyl]amino}-1H-benzimidazol-
1-yl)-3-phenylpropanoic acid L243 3-(6-{[(2E)-4-oxo-4-(2,3,4,5,6-
511 2.80 B I pentamethylphenyl)-2-butenoyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L244
3-(6-{[(6-bromo-2-oxo-2H-chromen-3- 534 2.65 B I
yl)carbonyl]amino}-1H-benzimidazol-1-yl)-3- phenylpropanoic acid
L245 3-phenyl-3-(6-{[4- 482 1.93 B I
(trifluoroacetyl)benzoyl]amino}-1H- benzimidazol-1-yl)propanoic
acid L246 3-[6-({[(4- 477 2.07 B I
chlorobenzoyl)amino]acetyl}amino)-1H-
benzimidazol-1-yl]-3-phenylpropanoic acid L247
3-(6-{[(2,7-dimethylpyrazolo[1,5- 455 1.82 B I
a]pyrimidin-6-yl)carbonyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L258
3-(6-{[2-(4-aminophenoxy)-2- 459 2.58 B I
methylpropanoyl]amino}-1H-benzimidazol-1- yl)-3-phenylpropanoic
acid L249 3-(6-{[(4-acetyl-5-methyl-2-oxo-2,3-dihydro- 462 1.81 B I
1H-pyrrol-3-yl)acetyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L250
3-phenyl-3-(6-{[(4-phenyl-1,2,3-thiadiazol-5- 470 2.26 B I
yl)carbonyl]amino}-1H-benzimidazol-1- yl)propanoic acid L251
3-[6-({[1-(4-chlorobenzyl)-5-oxo-3- 517 2.09, B I
pyrrolidinyl]carbonyl}amino)-1H- 2.14*
benzimidazol-1-yl]-3-phenylpropanoic acid L252 3-(6-{[({[(Z)-1-(4-
491 2.61, B I chlorophenyl)ethylidene]amino}oxy)acetyl]amino}-
2.73* 1H-benzimidazol-1-yl)-3- phenylpropanoic acid L253
3-phenyl-3-{6-[(1,2,3-thiadiazol-4- 394 1.71 B I
ylcarbonyl)amino]-1H-benzimidazol-1- yl}propanoic acid L254
3-(6-{[(5-chloro-1-benzothien-3- 490 2.53 B I
yl)acetyl]amino}-1H-benzimidazol-1-yl)-3- phenylpropanoic acid L255
3-[6-({[5-chloro-2-(methylsulfanyl)-4- 468 2.29 B I
pyrimidinyl]carbonyl}amino)-1H-
benzimidazol-1-yl]-3-phenylpropanoic acid L256
3-[6-({[1-(2-furylmethyl)-5-oxo-3- 473 1.78, B I
pyrrolidinyl]carbonyl}amino)-1H- 1.81*
benzimidazol-1-yl]-3-phenylpropanoic acid L257
3-(6-{[(3-tert-butyl-1-methyl-1H-pyrazol-5- 446 2.33 B I
yl)carbonyl]amino}-1H-benzimidazol-1-yl)-3- phenylpropanoic acid
L258 3-(6-{[(5-oxo-2- 393 1.31 B I pyrrolidinyl)carbonyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L259
3-(6-{[(2,5-dimethoxyphenyl)acetyl]amino}- 460 2.05 B I
1H-benzimidazol-1-yl)-3-phenylpropanoic acid L260
3-[6-({[2-(4-methylphenoxy)-3- 494 2.40 B I
pyridinyl]carbonyl}amino)-1H-benzimidazol- 1-yl]-3-phenylpropanoic
acid L261 3-[6-(2-methyl-6-nitro-4-oxo-3(4H)- 470 2.32 B I
quinazolinyl)-1H-benzimidazol-1-yl]-3- phenylpropanoic acid L262
3-(6-{[(3-methoxyphenyl)acetyl]amino}-1H- 430 2.01 B I
benzimidazol-1-yl)-3-phenylpropanoic acid L263
3-(6-{[(4-methoxyphenyl)acetyl]amino}-1H- 430 1.98 B I
benzimidazol-1-yl)-3-phenylpropanoic acid L264
3-(6-{[(2-methoxyphenyl)acetyl]amino}-1H- 430 2.04 B I
benzimidazol-1-yl)-3-phenylpropanoic acid L265 3-(6-{[(2-phenoxy-3-
479 2.24 B I pyridinyl)carbonyl]amino}-1H-benzimidazol-
1-yl)-3-phenylpropanoic acid L266
3-[6-({2-[4-(aminocarbonyl)phenoxy]-2- 488 1.81 B I
methylpropanoyl}amino)-1H-benzimidazol-1- yl]-3-phenylpropanoic
acid L267 3-phenyl-3-{6-[(1,2,3,4-tetrahydro-2- 440 2.41, B I
naphthalenylcarbonyl)amino]-1H- 2.55* benzimidazol-1-yl}propanoic
acid L268 3-(6-{[(3,5-dimethyl-4- 405 1.78 B I
isoxazolyl)carbonyl]amino}-1H- benzimidazol-1-yl)-3-phenylpropanoic
acid L269 3-phenyl-3-{6-[(1H-pyrrol-2- 375 1.78 B I
ylcarbonyl)amino]-1H-benzimidazol-1- yl}propanoic acid L270
3-[6-({[(2S)-5- 392 2.46 B I oxopyrrolidinyl]carbonyl}amino)-1H-
benzimidazol-1-yl]-3-phenylpropanoic acid L271
3-phenyl-3-[6-({[(3S,4R,5S)-3,4,5-trihydroxy- 438 0.93 B I
1-cyclohexen-1-yl]carbonyl}amino)-1H- benzimidazol-1-yl]propanoic
acid L272 3-{6-[(cyclohexylacetyl)amino]-1H- 406 2.31 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L273
3-phenyl-3-(6-{[4-(1H-pyrrol-1- 451 2.49 B I
yl)benzoyl]amino}-1H-benzimidazol-1- yl)propanoic acid L274
3-(6-{[(2,4-dihydroxy-5- 420 1.41 B I
pyrimidinyl)carbonyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L275
3-(6-{[2-(1,3-dioxo-1,3-dihydro-2H-isoindol- 483 1.97, B I
2-yl)propanoyl]amino}-1H-benzimidazol-1- 2.10*
yl)-3-phenylpropanoic acid L276
3-(6-{[3-(1,3-dioxo-1,3-dihydro-2H-isoindol- 483 1.93 B I
2-yl)propanoyl]amino}-1H-benzimidazol-1- yl)-3-phenylpropanoic acid
L277 3-[6-({[1-(4- 488 2.75 B I
chlorophenyl)cyclopentyl]carbonyl}amino)-
1H-benzimidazol-1-yl]-3-phenylpropanoic acid L278
3-(6-{[(4-oxo-2-thioxo-1,3-thiazolidin-3- 455 1.89 B I
yl)acetyl]amino}-1H-benzimidazol-1-yl)-3- phenylpropanoic acid L279
3-[6-({[(4S)-2,6-dioxohexahydro-4- 422 1.07 B I
pyrimidinyl]carbonyl}amino)-1H-
benzimidazol-1-yl]-3-phenylpropanoic acid L280
3-{6-[([1,1'-biphenyl]-4-ylacetyl)amino]-1H- 476 2.55 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L281
3-(6-{[(6-methoxy-3-oxo-2,3-dihydro-1H- 484 1.80, B I
inden-1-yl)acetyl]amino}-1H-benzimidazol-1- 1.92*
yl)-3-phenylpropanoic acid L282
3-{6-[(9H-fluoren-9-ylacetyl)amino]-1H- 488 2.59 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L283
3-(6-{[(9-oxo-9H-fluoren-1- 488 2.58 B I
yl)carbonyl]amino}-1H-benzimidazol-1-yl)-3- phenylpropanoic acid
L284 3-(6-{[(2-nitrophenyl)acetyl]amino}-1H- 445 2.08 B I
benzimidazol-1-yl)-3-phenylpropanoic acid L285
3-(6-{[(4-nitrophenyl)acetyl]amino}-1H- 446 1.99 B I
benzimidazol-1-yl)-3-phenylpropanoic acid L286
3-{6-[(9-anthrylcarbonyl)amino]-1H- 486 2.56 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L287
3-(6-{[(2-methylphenyl)acetyl]amino}-1H- 414 2.19 B I
benzimidazol-1-yl)-3-phenylpropanoic acid L288
3-(6-{[(2,6-dioxo-1,2,3,6-tetrahydro-4- 420 1.27 B I
pyrimidinyl)carbonyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L289
3-(6-{[(4-methylphenyl)acetyl]amino}-1H- 414 2.21 B I
benzimidazol-1-yl)-3-phenylpropanoic acid L290
3-{6-[(3-methylbenzoyl)amino]-1H- 400 2.19 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L291
3-phenyl-3-{6-[(4-vinylbenzoyl)amino]-1H- 412 2.35 B I
benzimidazol-1-yl}propanoic acid L292
3-{6-[(4-methylbenzoyl)amino]-1H- 400 2.17 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L293
3-{6-[(2-methylbenzoyl)amino]-1H- 400 2.07 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L294
3-(6-{[(3-methylphenyl)acetyl]amino}-1H- 414 2.21 B I
benzimidazol-1-yl)-3-phenylpropanoic acid L295
3-(6-{[(3-nitrophenyl)acetyl]amino}-1H- 445 2.05 B I
benzimidazol-1-yl)-3-phenylpropanoic acid L296
3-{6-[(4-bromobenzoyl)amino]-1H- 464 2.40 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L297
3-phenyl-3-{6-[(9H-xanthen-9- 490 2.57 B I
ylcarbonyl)amino]-1H-benzimidazol-1- yl}propanoic acid L298
3-{6-[(2-phenoxypropanoyl)amino]-1H- 430 2.08, B I
benzimidazol-1-yl}-3-phenylpropanoic acid 2.20* L299
3-(6-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2- 469 1.94 B I
yl)acetyl]amino}-1H-benzimidazol-1-yl)-3- phenylpropanoic acid L300
3-{6-[(1,3-benzodioxol-5-ylcarbonyl)amino]- 430 1.92 B I
1H-benzimidazol-1-yl}-3-phenylpropanoic acid L301
3-phenyl-3-{6-[(phenylacetyl)amino]-1H- 400 2.06 B I
benzimidazol-1-yl}propanoic acid L302
3-{6-[(bicyclo[2.2.1]hept-5-en-2- 402 2.23 B I
ylcarbonyl)amino]-1H-benzimidazol-1-yl}-3- phenylpropanoic acid
L303 3-(6-{[hydroxy(phenyl)acetyl]amino}-1H- 416 1.85 B I
benzimidazol-1-yl)-3-phenylpropanoic acid L304
3-(6-{[(2-naphthyloxy)acetyl]amino}-1H- 466 2.53 B I
benzimidazol-1-yl)-3-phenylpropanoic acid L305 3-phenyl-3-(6-{[(1-
454 2.53 B I phenylcyclopentyl)carbonyl]amino}-1H-
benzimidazol-1-yl)propanoic acid L306 3-phenyl-3-{6-[(tetrahydro-2-
380 1.63 B I furanylcarbonyl)amino]-1H-benzimidazol-1- yl}propanoic
acid L307 3-(6-{[cyclopentyl(phenyl)acetyl]amino}-1H- 468 2.66 B I
benzimidazol-1-yl)-3-phenylpropanoic acid L308
3-{6-[(4-tert-butylbenzoyl)amino]-1H- 442 2.65 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L309
3-{6-[(1-adamantylcarbonyl)amino]-1H- 445 2.57 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L310
3-{6-[(4-methoxybenzoyl)amino]-1H- 416 1.98 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L311
3-{6[(4-cyclohexylbenzoyl)amino]-1H- 468 2.93 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L312
3-[6-(1-naphthoylamino)-1H-benzimidazol-1- 436 2.50 B I
yl]-3-phenylpropanoic acid L313
3-[6-(benzoylamino)-1H-benzimidazol-1-yl]- 386 2.01 B I
3-phenylpropanoic acid L314 3-{6-[(5-isoxazolylcarbonyl)amino]-1H-
377 1.65 B I benzimidazol-1-yl}-3-phenylpropanoic acid L315
3-(6-{[(2E)-3-(4-bromophenyl)-2- 492 2.57, B I
propenoyl]amino}-1H-benzimidazol-1-yl)-3- 2.72* phenylpropanoic
acid L316 3-{6-[(3-bromo-4-methoxybenzoyl)amino]- 494 2.33 B I
1H-benzimidazol-1-yl}-3-phenylpropanoic acid L317
3-{6-[(4-butylbenzoyl)amino]-1H- 442 2.73 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L318
3-(6-{[4-(dimethylamino)benzoyl]amino}- 429 2.09 B I
1H-benzimidazol-1-yl)-3-phenylpropanoic acid L319
3-(6-{[(4-bromo-1-ethyl-3-methyl-1H- 496 2.06 B I
pyrazol-5-yl)carbonyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L320
3-{6-[(4-nitrobenzoyl)amino]-1H- 431 2.08 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L321
3-(6-{[(2-cyclopropyl-4- 477 1.92 B I
quinolinyl)carbonyl]amino}-1H- benzimidazol-1-yl)-3-phenylpropanoic
acid L322 3-phenyl-3-[6-({[2-(2-thienyl)-4- 519 2.66 B I
quinolinyl]carbonyl}amino)-1H- benzimidazol-1-yl]propanoic acid
L323 3-{6-[(3,5-dinitrobenzoyl)amino]-1H- 476 2.36 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L324
3-phenyl-3-{6-[(3-phenyl-2- 410 2.36 B I
propynoyl)amino]-1H-benzimidazol-1- yl}propanoic acid L325
3-{6-[(4-fluoro-1-naphthoyl)amino]-1H- 454 2.41 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L326
3-(6-{[(acetylamino)acetyl]amino}-1H- 381 1.06 B I
benzimidazol-1-yl)-3-phenylpropanoic acid L327
3-(6-{[(7-methyl-2-phenyl-4- 527 2.77 B I
quinolinyl)carbonyl]amino}-1H- benzimidazol-1-yl)-3-phenylpropanoic
acid L328 3-(6-{[(5-bromo-4-methoxy-3- 500 (-ve) 2.11 B I
thienyl)carbonyl]amino}-1H-benzimidazol-1- yl)-3-phenylpropanoic
acid L329 3-{6-[(4-[1,1'-biphenyl]-4-yl-4- 518 2.62 B I
oxobutanoyl)amino]-1H-benzimidazol-1-yl}- 3-phenylpropanoic acid
L330 3-{6-[(1-cyclohexen-1-ylcarbonyl)amino]-1H- 390 2.10 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L331
3-(6-{[(4-bromophenyl)acetyl]amino}-1H- 478 2.39 B I
benzimidazol-1-yl)-3-phenylpropanoic acid L332
3-(6-{[2-(methylsulfanyl)benzoyl]amino}-1H- 432 2.11 B I
benzimidazol-1-yl)-3-phenylpropanoic acid L333
3-(6-{[(2E)-3-(5-bromo-2-ethoxyphenyl)-2- 536 2.60, B I
propenoyl]amino}-1H-benzimidazol-1-yl)-3- 2.74* phenylpropanoic
acid L334 3-(6-{[4-(methylsulfonyl)benzoyl]amino}- 464 1.78 B I
1H-benzimidazol-1-yl)-3-phenylpropanoic acid L335 3-(6-{[2-nitro-4-
499 2.42 B I (trifluoromethyl)benzoyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L336
3-{6-[([1,1'-biphenyl]-4-ylcarbonyl)amino]- 462 2.61 B I
1H-benzimidazol-1-yl}-3-phenylpropanoic acid L337
3-{6-[(4-benzoylbenzoyl)amino]-1H- 490 2.53 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L338 3-phenyl-3-(6-{[4-
454 2.45 B I (trifluoromethyl)benzoyl]amino}-1H-
benzimidazol-1-yl)propanoic acid L339
3-{6-[(4-acetylbenzoyl)amino]-1H- 429 1.94 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L340
3-{6-[(4-cyanobenzoyl)amino]-1H- 411 2.00 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L341 3-(6-{[2,4- 522 2.59
B I bis(trifluoromethyl)benzoyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L342 3-phenyl-3-(6-{[3-
454 2.42 B I (trifluoromethyl)benzoyl]amino}-1H-
benzimidazol-1-yl)propanoic acid L343
3-{6-[(3-cyanobenzoyl)amino]-1H- 411 2.02 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L344
3-(6-{[4-(3-methyl-5-oxo-4,5-dihydro-1H- 482 1.79 B I
pyrazol-1-yl)benzoyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L345
3-{6-[(1H-benzimidazol-5-ylcarbonyl)amino]- 426 1.12 B I
1H-benzimidazol-1-yl}-3-phenylpropanoic acid L346
3-{6-[(diphenylacetyl)amino]-1H- 476 2.58 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L347
3-{6-[(2-hydroxybenzoyl)amino]-1H- 402 2.12 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L348
3-{6-[(4-ethylbenzoyl)amino]-1H- 414 2.37 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L349
3-(6-{[3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- 433 1.57 B I
yl)propanoyl]amino}-1H-benzimidazol-1-yl)- 3-phenylpropanoic acid
L350 3-{6-[(3-bromo-2,6- 526 2.24 B I
dimethoxybenzoyl)amino]-1H-benzimidazol- 1-yl}-3-phenylpropanoic
acid L351 3-{6-[(4-bromo-2,3,5,6- 538 2.57 B I
tetrafluorobenzoyl)amino]-1H-benzimidazol- 1-yl}-3-phenylpropanoic
acid L352 3-{6-[(5-bromo-2-furoyl)amino]-1H- 454 2.09 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L353
3-{6-[(3-iodobenzoyl)amino]-1H- 512 2.49 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L354
3-{6-[(2-formylbenzoyl)amino]-1H- 414 1.81 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L355
3-{6-[(2-bromobenzoyl)amino]-1H- 464 2.08 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L356
3-{6-[(3-bromobenzoyl)amino]-1H- 466 2.40 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L357 3-(6-{[(5-bromo-3-
467 2.00 B I pyridinyl)carbonyl]amino}-1H-benzimidazol-
1-yl)-3-phenylpropanoic acid L358
3-(6-{[(5-bromo-2-thienyl)carbonyl]amino}- 472 2.37 B I
1H-benzimidazol-1-yl)-3-phenylpropanoic acid L359
3-{6-[(2-bromo-5-methoxybenzoyl)amino]- 494 2.18 B I
1H-benzimidazol-1-yl}-3-phenylpropanoic acid L360
3-{6-[(4-bromo-2-methylbenzoyl)amino]-1H- 478 2.41 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L361
3-{6-[(4-bromo-2-chlorobenzoyl)amino]-1H- 500 2.51 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L362
3-(6-{[(2E)-3-(3-bromo-4-fluorophenyl)-2- 510 2.55 B I
propenoyl]amino}-1H-benzimidazol-1-yl)-3- phenylpropanoic acid L363
3-(6-{[(2E)-3-(6-bromo-1,3-benzodioxol-5- 536 2.48, B I
yl)-2-propenoyl]amino}-1H-benzimidazol-1- 2.60*
yl)-3-phenylpropanoic acid L364
3-{6-[(2-oxo-3-phenylpropanoyl)amino]-1H- 429 2.58 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L365
3-{6-[(4-oxopentanoyl)amino]-1H- 380 1.44 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L366
3-phenyl-3-[6-({[2-(phenylsulfanyl)-3- 495 2.17 B I
pyridinyl]carbonyl}amino)-1H-benzimidazol- 1-yl]propanoic acid L367
3-{6-[(2-hydroxy-5-nitrobenzoyl)amino]-1H- 447 2.25 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L368
3-{6-[(2-hydroxy-3-methoxybenzoyl)amino]- 432 2.18 B I
1H-benzimidazol-1-yl}-3-phenylpropanoic acid L369
3-(6-{[(4-hydroxy-3- 446 1.70 B I methoxyphenyl)acetyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L370
3-{6-[(2,5-dihydroxybenzoyl)amino]-1H- 418 1.84 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L371
3-{6-[(2-hydroxy-3-methylbenzoyl)amino]- 416 2.47 B I
1H-benzimidazol-1-yl}-3-phenylpropanoic acid L372
3-{6-[(3-hydroxy-4-methylbenzoyl)amino]- 416 1.89 B I
1H-benzimidazol-1-yl}-3-phenylpropanoic acid L373
3-(6-{[(3-hydroxy-4- 446 1.75 B I methoxyphenyl)acetyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L374
3-(6-{[(4,7-dimethylpyrazolo[5,1- 456 1.78 B I
c][1,2,4]triazin-3-yl)carbonyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L375 3-(6-{[3-(2,4- 446
1.67 B I dihydroxyphenyl)propanoyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L376
3-(6-{[(3,5-ditert-butyl-4- 528 2.81 B I
hydroxyphenyl)acetyl]amino}-1H-
benzimidazol-1-yl)-3-phenylpropanoic acid L377
3-(6-{[(6-hydroxy-2,5,7,8-tetramethyl-3,4- 514 2.42 B I
dihydro-2H-chromen-2-yl)carbonyl]amino}-
1H-benzimidazol-1-yl)-3-phenylpropanoic acid L378
3-{6-[(5-formyl-2-hydroxybenzoyl)amino]- 430 2.03 B I
1H-benzimidazol-1-yl}-3-phenylpropanoic acid L379
3-{6-[(3,5-dichloro-2- 470 2.79 B I
hydroxybenzoyl)amino]-1H-benzimidazol-1- yl}-3-phenylpropanoic acid
L380 3-phenyl-3-{6-[(2,4,6- 434 1.88 B I
trihydroxybenzoyl)amino]-1H-benzimidazol- 1-yl}propanoic acid L381
3-{6-[(2-hydroxybenzoyl)amino]-1H- 402 2.06 B I
benzimidazol-1-yl}-3-phenylpropanoic acid L382
3-phenyl-3-{6-[(2,3,5-trichloro-6- 506 2.35 B I
hydroxybenzoyl)amino]-1H-benzimidazol-1- yl}propanoic acid L383
3-{6-[(5-chloro-2-hydroxybenzoyl)amino]- 436 2.38 B I
1H-benzimidazol-1-yl}-3-phenylpropanoic acid L384
3-{6-[(5-bromo-2-hydroxybenzoyl)amino]- 482 2.47 B I
1H-benzimidazol-1-yl}-3-phenylpropanoic acid L385
3-{6-[(2-hydroxy-4-methylbenzoyl)amino]- 416 2.3 B I
1H-benzimidazol-1-yl}-3-phenylpropanoic acid L386
3-(6-{[(3,4-dihydroxyphenyl)acetyl]amino}- 432 1.54 B I
1H-benzimidazol-1-yl)-3-phenylpropanoic acid L387
3-{6-[(2-fluoro-6-iodobenzoyl)amino]-1H- 530 2.14 B I
benzimidazol-1-yl}-3-phenylpropanoic acid
* * * * *